Aging

Ganxun Li1, * , Tongtong Liu2, * , Guannan Jin3, * , Tianhong Li4, * , Junnan Liang1 , Qian Chen5 , Lin Chen1 , Wei Wang1 , Yuwei Wang1 , Jia Song1 , Huifang Liang1 , Chuanhan Zhang2 , Peng Zhu1 , Wanguang Zhang1 , Zeyang Ding1 , Xiaoping Chen1 , Bixiang Zhang1 , Tongji Multidisciplinary Team for Treating COVID-19 (TTTC)

doi : 10.18632/aging.203653

Volume 13, Issue 20 pp 23442—23458

Hyperamylasemia was found in a group of patients with COVID-19 during hospitalization. However, the evolution and the clinical significance of hyperamylasemia in COVID-19, is not well characterized.

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COVID-19: risk factors for severe cases of the Delta variant

Kaiyuan Hu1 , Liu Lin1 , Ying Liang1 , Xinning Shao1 , Zhongwei Hu1 , Hongbin Luo1 , Ming Lei1

doi : 10.18632/aging.203655

Volume 13, Issue 20 pp 23459—23470

Since April 2021, the SARS-CoV-2 (B.1.167) Delta variant has been rampant worldwide. Recently, this variant has spread in Guangzhou, China. Our objective was to characterize the clinical features and risk factors of severe cases of the Delta variant in Guangzhou.

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Predicting physiological aging rates from a range of quantitative traits using machine learning

Eric D. Sun1 , Yong Qian1 , Richard Oppong1 , Thomas J. Butler1 , Jesse Zhao1 , Brian H. Chen2 , Toshiko Tanaka1 , Jian Kang3 , Carlo Sidore4 , Francesco Cucca4 , Stefania Bandinelli5 , Gonçalo R. Abecasis3 , Myriam Gorospe6 , Luigi Ferrucci1 , David Schlessinger6 , Ilya Goldberg7 , Jun Ding1

doi : 10.18632/aging.203660

Volume 13, Issue 20 pp 23471—23516

It is widely thought that individuals age at different rates. A method that measures “physiological age” or physiological aging rate independent of chronological age could therefore help elucidate mechanisms of aging and inform an individual’s risk of morbidity and mortality. Here we present machine learning frameworks for inferring individual physiological age from a broad range of biochemical and physiological traits including blood phenotypes (e.g., high-density lipoprotein), cardiovascular functions (e.g., pulse wave velocity) and psychological traits (e.g., neuroticism) as main groups in two population cohorts SardiNIA (~6,100 participants) and InCHIANTI (~1,400 participants). The inferred physiological age was highly correlated with chronological age (R2 > 0.8). We further defined an individual’s physiological aging rate (PAR) as the ratio of the predicted physiological age to the chronological age. Notably, PAR was a significant predictor of survival, indicating an effect of aging rate on mortality. Our trait-based PAR was correlated with DNA methylation-based epigenetic aging score (r = 0.6), suggesting that both scores capture a common aging process. PAR was also substantially heritable (h2~0.3), and a subsequent genome-wide association study of PAR identified significant associations with two genetic loci, one of which is implicated in telomerase activity. Our findings support PAR as a proxy for an underlying whole-body aging mechanism. PAR may thus be useful to evaluate the efficacy of treatments that target aging-related deficits and controllable epidemiological factors.

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A genetic determinant of VEGF-A levels is associated with telomere attrition

Vesna Gorenjak1, *,# , Alexandros M. Petrelis1, *,# , Maria G. Stathopoulou1, * , Simon Toupance2, * , Satish Kumar1 , Carlos Labat2 , Christine Masson1 , Helena Murray3 , John Lamont3 , Peter Fitzgerald3 , Athanase Benetos2,4, * , Sophie Visvikis-Siest1, * , TELARTA consortium

doi : 10.18632/aging.203636

Volume 13, Issue 20 pp 23517—23526

Telomere length (TL) is a hallmark of cellular aging and is associated with chronic diseases development. The vascular endothelial growth factor A (VEGF-A), a potent angiogenesis factor, is implicated in the pathophysiology of many chronic diseases. The aim of the present study was to investigate the associations between VEGF-A and TL.

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NEOage clocks - epigenetic clocks to estimate post-menstrual and postnatal age in preterm infants

Stefan Graw1 , Marie Camerota2 , Brian S. Carter3 , Jennifer Helderman4 , Julie A. Hofheimer5 , Elisabeth C. McGowan6 , Charles R. Neal7 , Steven L. Pastyrnak8 , Lynne M. Smith9 , Sheri A. DellaGrotta10 , Lynne M. Dansereau10 , James F. Padbury6 , Michael O’Shea5 , Barry M. Lester2,6,10,11 , Carmen J. Marsit1 , Todd M. Everson1

doi : 10.18632/aging.203637

Volume 13, Issue 20 pp 23527—23544

Epigenetic clocks based on DNA methylation (DNAm) can accurately predict chronological age and are thought to capture biological aging. A variety of epigenetic clocks have been developed for different tissue types and age ranges, but none have focused on postnatal age prediction for preterm infants. Epigenetic estimators of biological age might be especially informative in epidemiologic studies of neonates since DNAm is highly dynamic during the neonatal period and this is a key developmental window. Additionally, markers of biological aging could be particularly important for those born preterm since they are at heightened risk of developmental impairments. We aimed to fill this gap by developing epigenetic clocks for neonatal aging in preterm infants.

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Profound synchrony of age-specific incidence rates and tumor suppression for different cancer types as revealed by the multistage-senescence model of carcinogenesis

Richard B. Richardson1,2 , Catalina V. Anghel3 , Dennis S. Deng3

doi : 10.18632/aging.203651

Volume 13, Issue 20 pp 23545—23578

The age-specific trend of cancer incidence rates, but not its magnitude, is well described employing the multistage theory of carcinogenesis by Armitage and Doll in combination with the senescence model of Pompei and Wilson. We derived empirical parameters of the multistage-senescence model from U.S. Surveillance, Epidemiology, and End Results (SEER) incidence data from 2000–2003 and 2010–2013 for The Cancer Genome Atlas (TCGA) cancer types. Under the assumption of a constant tumor-specific transition rate between stages, there is an extremely strong linear relationship (P < 0.0001) between the number of stages and the stage transition rate. The senescence tumor suppression factor for 20 non-reproductive cancers is remarkably consistent (0.0099±0.0005); however, five female reproductive cancers have significantly higher tumor suppression. The peak incidence rate for non-reproductive cancers occurs at a younger age for cancers with fewer stages and their carcinogenic stages are of longer duration. Driver gene mutations are shown to contribute on average only about a third of the carcinogenic stages of different tumor types. A tumor’s accumulated incidence, calculated using a two-variable (age, stage) model, is strongly associated with intrinsic cancer risk. During both early adulthood and senescence, the pace of tumor suppression appears to be synchronized across most cancer types, suggesting the presence of overlapping evolutionary processes.

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AHNAK suppresses ovarian cancer progression through the Wnt/?-catenin signaling pathway

Yanlin Cai1 , Yi Hu1 , Furong Yu1 , Wenjuan Tong1 , Shufen Wang1 , Shunliang Sheng1 , Jiayu Zhu2

doi : 10.18632/aging.203473

Volume 13, Issue 20 pp 23579—23587

Globally, ovarian cancer is the 2nd most frequent cause of gynecologic-associated cancer fatalities among women. It has an unfavorable prognosis. There is a need to elucidate on the mechanisms involved in ovarian cancer progression and to identify novel cancer targets. We investigated and verified AHNAK contents in ovarian cancer tissues and corresponding healthy tissues. Then, we overexpressed AHNAK in vitro and in vivo to establish the roles of AHNAK in ovarian cancer cell proliferation and metastasis. Finally, we evaluated the possible molecular mechanisms underlying. We established that AHNAK was downregulated in ovarian cancer. Elevated AHNAK contents in ovarian cancer cell lines remarkably repressed ovarian cancer cell growth, along with metastasis in vitro, as well as in vivo. Moreover, AHNAK suppressed the progress of ovarian cancer partly via dampening the Canonical Wnt cascade. Therefore, AHNAK may be a biomarker and treatment target for ovarian cancer.

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ALDH2 promotes uterine corpus endometrial carcinoma proliferation and construction of clinical survival prognostic model

Yun-Qian Cui1, * , Yuan Xiang2, * , Fei Meng1 , Chun-Hui Ji1 , Rui Xiao4 , Jia-Peng Li3 , Zhou-Tong Dai3 , Xing-Hua Liao3

doi : 10.18632/aging.203605

Volume 13, Issue 20 pp 23588—23602

UCEC is one of the three common malignant tumors of the female reproductive tract. According to reports, the cure rate of early UCEC can reach 95%. Therefore, the development of prognostic markers will help UCEC patients to find the disease earlier and develop treatment earlier. The ALDH family was first discovered to be the essential gene of the ethanol metabolism pathway in the body. Recent studies have shown that ALDH can participate in the regulation of cancer. In our research, we explored the expression of the ALDH family in 33 cancers. It was found that ALDH2 was abnormally expressed in UCEC. Besides, in vivo and in vitro experiments were conducted to explore the effect of ALDH2 expression on the proliferation of UCEC cell lines. Meanwhile, the change of its expression is not due to gene mutations, but is regulated by miR-135-3p. At the same time, the impact of ALDH2 changes on the survival of UCEC patients is deeply discussed. Finally, a nomogram for predicting survival was constructed, with a C-index of 0.798 and AUC of 0.764. This study suggests that ALDH2 may play a crucial role in UCEC progression and has the potential as a prognostic biomarker of UCEC.

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Resveratrol promotes axonal regeneration after spinal cord injury through activating Wnt/?-catenin signaling pathway

Zimin Xiang1,2,3, * , Shuai Zhang1,2,3, * , Xiaodong Yao1,2,3 , Libin Xu1,2,3 , Jianwei Hu1,2,3 , Chenghui Yin1,2,3 , Jianmei Chen1,2,3 , Hao Xu1,2,3

doi : 10.18632/aging.203628

Volume 13, Issue 20 pp 23603—23619

Spinal cord injury (SCI) is characterized by autonomic dysreflexia, chronic pain, sensory and motor deficits. Resveratrol has shown potential neuroprotective function in several neurodegenerative diseases’ models. However, if resveratrol could improve the function recovery after SCI and the further mechanism have not been investigated.

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Nmnat2 attenuates amyloidogenesis and up-regulates ADAM10 in AMPK activity-dependent manner

Xiang-Shu Cheng1,2,4, * , Fang-Xiao Shi2, * , Kun-Peng Zhao2,7, * , Wang Lin2 , Xiao-Ying Li1 , Jun Zhang1 , Yao-Yao Bu1 , Rui Zhu2 , Xiao-Hong Li2 , Dong-Xiao Duan2,5 , Xin-Ying Ji6 , Jian-She Wei4 , Jian-Zhi Wang2 , Jin Du1,3,4, & , Xin-Wen Zhou2

doi : 10.18632/aging.203634

Volume 13, Issue 20 pp 23620—23636

Amyloid-? (A?) accumulating is considered as a causative factor for formation of senile plaque in Alzheimer’s disease (AD), but its mechanism is still elusive. The Nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2), a key redox cofactor for energy metabolism, is reduced in AD. Accumulative evidence has shown that the decrease of ?-secretase activity, a disintegrin and metalloprotease domain 10 (ADAM10), is responsible for the increase of A? productions in AD patient’s brain. Here, we observe that the activity of ?-secretase ADAM10 and levels of Nmnat2 are significantly decreased, meanwhile there is a simultaneous elevation of A? in Tg2576 mice. Over-expression of Nmnat2 increases the mRNA expression of ?-secretase ADAM10 and its activity and inhibits A? production in N2a/APPswe cells, which can be abolished by Compound C, an AMPK antagonist, suggesting that AMPK is involved in over-expression of Nmnat2 against A? production. The further assays demonstrate that Nmnat2 activates AMPK by up-regulating the ratio of NAD+/NADH, moreover AMPK agonist AICAR can also increase ADAM10 activity and reduces A?1-40/1-42. Taken together, Nmnat2 suppresses A? production and up-regulates ADAM10 in AMPK activity-dependent manner, suggesting that Nmnat2 may serve as a new potential target in arresting AD.

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Comprehensive analysis of prognostic genes in gastric cancer

Shaohua Huang1, * , Liping Ma2, * , Biyang Lan1 , Ning Liu1 , Wenwei Nong1 , Zhihu Huang2

doi : 10.18632/aging.203638

Volume 13, Issue 20 pp 23637—23651

Gastric cancer is associated with high mortality, and effective methods for predicting prognosis are lacking. We aimed to identify potential prognostic markers associated with the development of gastric cancer through bioinformatic analyses.

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Up-regulation of SIRT1 induced by 17beta-estradiol promotes autophagy and inhibits apoptosis in osteoblasts

Yu Wang1, * , Runhong Mei1,2, * , Shimin Hao1 , Peng Luo1 , Penghao Wang1 , Yaser Almatari1 , Lei Guo1 , Lan Guo1

doi : 10.18632/aging.203639

Volume 13, Issue 20 pp 23652—23671

Osteoporosis is a common systemic skeletal metabolism disorder resulting in bone fragility and increased fracture risk. Silent information regulator factor 2 homolog 1 (SIRT1) is crucial in the regulation of several biological processes, including bone metabolism, autophagy, apoptosis, and aging. This study aimed to assess whether the up-regulation of SIRT1 induced by 17beta-estradiol (17?-E2) could promote autophagy and inhibit apoptosis in osteoblasts via the AMPK-mTOR and FOXO3a pathways, respectively. The study found that 17?-E2 (10-6 M) administration induced the up-regulation of SIRT1 in osteoblasts. Up-regulation of SIRT1 induced by 17?-E2 increased the expression level of LC3, Beclin-1, Bcl-2, p-AMPK, FOXO3a but decreased caspase-3 and p-mTOR expression, and then promoted autophagy and inhibited apoptosis. More autophagosomes were observed under a transmission electron microscope (TEM) in 17?-E2 and SRT1720 (a selective SIRT1 activator) co-treated group. When Ex527 (a SIRT1-specific inhibitor) was pretreated, the reversed changes were observed. Taken together, our findings demonstrated that the up-regulation of SIRT1 induced by 17?-E2 could promote autophagy via the AMPK-mTOR pathway and inhibit apoptosis via the FOXO3a activation in osteoblasts, and SIRT1 might become a more significant target in osteoporosis treatment.

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Differences in and verification of genetic alterations in chemotherapy and immunotherapy for metastatic melanoma

Yang Li1 , Yuling Gao1 , Weiling Chu1 , Jianjian Lv2 , Zhi Li1 , Tongxin Shi1

doi : 10.18632/aging.203640

Volume 13, Issue 20 pp 23672—23688

Metastatic melanoma has poor therapeutic response and may present resistance to chemotherapy or immunotherapy. Significant differences are observed in the survival time of patients with metastatic melanoma based on the administration of chemotherapy or immunotherapy; thus, we have explored the important role of specific differential genes between the two therapies in their effect on treatment response in melanoma.

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Analysis of gut microbiota and metabolites in patients with rheumatoid arthritis and identification of potential biomarkers

Yumei Chen1 , Chiyu Ma1,4 , Lixiong Liu2 , Jingquan He1 , Chengxin Zhu1 , Fengping Zheng1 , Weier Dai3 , Xiaoping Hong2 , Dongzhou Liu2, & , Donge Tang1 , Yong Dai1,4

doi : 10.18632/aging.203641

Volume 13, Issue 20 pp 23689—23701

Rheumatoid arthritis (RA) is an autoimmune disease described by joint destruction, synovitis and pannus formation. The gut microbiota acts as an environmental factor that plays an important role in RA, but little research regarding the etiopathogenic mechanisms of the microbiome in RA has been carried out. We used an integrated approach of 16S rRNA gene sequencing and ultrahigh-performance liquid chromatography-mass spectrometry-based metabolomics to analyze the structure and diversity of the intestinal flora and metabolites of the gut microbiota in RA patients compared with healthy subjects. In this study, ?-diversity analysis of the gut microbiota showed that there was no significant difference between the healthy control (HC) and RA groups. However, ?-diversity analysis showed that there was a significant difference between the two groups. Further analysis of alteration of the gut microbiota revealed that at the phylum level, the relative abundance of p_Bacteroidetes was significantly decreased in the RA group, while that of Verrucomicrobia and Proteobacteria was significantly increased in the RA group. At the genus level, Bacteroides, Faecalibacterium and some probiotics were decreased in the RA group, while 97 genera, including Lactobacillus, Streptococcus and Akkermansia, were increased in the RA group. Seventy-four differentially abundant metabolites were identified between the HC and RA groups, and we identified two potential biomarkers (9,12-octadecadiynoic acid and 10Z-nonadecenoic acid) in RA.

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Selected ideal natural ligand against TNBC by inhibiting CDC20, using bioinformatics and molecular biology

Naimeng Liu1 , Xinhui Wang2 , Zhu Zhu1 , Duo Li4 , Xiaye Lv3 , Yichang Chen1 , Haoqun Xie5 , Zhen Guo5 , Dong Song1

doi : 10.18632/aging.203642

Volume 13, Issue 20 pp 23702—23725

Find potential therapeutic targets of triple-negative breast cancer (TNBC) patients by bioinformatics. Screen ideal natural ligand that can bind with the potential target and inhibit it by using molecular biology.

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Exosome long non-coding RNA SOX2-OT contributes to ovarian cancer malignant progression by miR-181b-5p/SCD1 signaling

Yongjing Lai1 , Lihua Dong1 , Huifang Jin1 , Hongju Li2 , Meiling Sun1 , Jianlan Li3

doi : 10.18632/aging.203645

Volume 13, Issue 20 pp 23726—23738

Ovarian cancer is a common gynecologic cancer with increased mortality and morbidity. Exosome-delivered long non-coding RNAs have been well found in cancer development. However, the function of exosomal SOX2-OT in ovarian cancer development is still unreported. In the present study, we were interested in the investigation of the effect of exosomal SOX2-OT during ovarian cancer pathogenesis. Significantly, we revealed that the SOX2-OT expression levels were up-regulated in the ovarian cancer patients’ plasma exosomes. The depletion of exosomal SOX2-OT inhibited migration, invasion, and proliferation and induced apoptosis in ovarian cancer cells. In mechanical exploration, SOX2-OT could sponge miR-181b-5p, and miR-181b-5p was able to target SCD1 in the ovarian cancer cells. The SCD1 overexpression and miR-181b-5p inhibitor could reverse exosomal SOX2-OT-mediated ovarian cancer progression. Functionally, the depletion of exosomal SOX2-OT significantly reduced tumor growth of ovarian cancer cells in vivo. In summary, we concluded that exosomal SOX2-OT enhanced ovarian cancer malignant phenotypes by miR-181b-5p/SCD1 axis. Our finding presents novel insights into the mechanism by which exosomal lncRNA SOX2-OT promotes ovarian cancer progression. SOX2-OT, miR-181b-5p, and SCD1 may serve as potential targets for the treatment of ovarian cancer.

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Loganin substantially ameliorates molecular deficits, pathologies and cognitive impairment in a mouse model of Alzheimer’s disease

Lulin Nie1, * , Kaiwu He1,2, * , Fengzhu Xie3 , Shifeng Xiao4 , Shupeng Li2 , Jia Xu1,5 , Kaiqin Zhang1,6 , Chen Yang1 , Li Zhou1 , Jianjun Liu1 , Liangyu Zou7 , Xifei Yang1

doi : 10.18632/aging.203646

Volume 13, Issue 20 pp 23739—23756

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease threatening the health of the elderly, but the available therapeutic and preventive drugs remain suboptimal. Loganin, an iridoid glycoside extracted from Cornus officinalis, is reported to have anti-inflammatory and memory-enhancing properties. This study is aimed to explore the influence of loganin on cognitive function in 3xTg-AD mice and the underlying mechanism associated with its neuroprotection. According to the results of behavioral tests, we found that administration of loganin could significantly alleviate anxiety behavior and improve memory deficits of 3xTg-AD mice. Furthermore, immunohistochemical analysis displayed that there were decreased A? deposition in the hippocampus and cortex of 3xTg-AD mice treated with loganin compared with the control mice. Importantly, the A?-related pathological change was mainly involved in altering APP expression and processing. And loganin was also found to reduce the levels of phosphorylated tau (i.e. pTauS396 and pTauS262) in 3xTg-AD mice. By performing 2D-DIGE combined with MALDI-TOF-MS/MS, we revealed 28 differentially expressed proteins in the 3xTg-AD mice treated with loganin compared with the control mice. Notably, 10 proteins largely involved in energy metabolism, synaptic proteins, inflammatory response, and ATP binding were simultaneously detected in 3xTg-AD mice compared to WT mice. The abnormal changes of energy metabolism (PAGM1 and ENO1), synaptic proteins (SYN2 and Cplx2), inflammatory response (1433Z) were verified by western blot. Overall, our study suggested that loganin could be used as a feasible candidate drug to ameliorate molecular deficits, pathologies and cognitive impairment for prevention and treatment of AD.

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Circular RNA circPRKCI contributes to malignant progression of T-cell acute lymphoblastic leukemia by modulating miR-20a-5p/SOX4 axis

Yan Zheng1 , Ben Niu1 , Weihua Zhang1 , Xingli Ru1 , Ying Gao1, & , Chuancui Li2 , Xifeng Wu2

doi : 10.18632/aging.203647

Volume 13, Issue 20 pp 23757—23768

Circular RNAs (circRNAs) have demonstrated critical roles in the development of cancers. This study aimed to explore the function of circular RNA circPRKCI/miR-20a-5p/SOX4 axis in acute lymphoblastic leukemia (ALL). Our data showed that the expression of circPRKCI and SOX4 was enhanced while the expression of miR-20a-5p was reduced in the clinical T-ALL samples. The expression of miR-20a-5p was negatively associated with circPRKCI and SOX4 in the T-ALL patients and the expression of circPRKCI was positive correlated with SOX4 in the T-ALL patients. Functionally, the silencing of circPRKCI suppressed the viability of T-ALL cells. Conversely, the knockdown of circPRKCI promoted the apoptosis of T-ALL cells. The levels of cleaved PARP and cleaved caspase3 were induced by the depletion of circPRKCI in T-ALL cells. Mechanically, the luciferase activity of circPRKCI was significantly decreased in T-ALL cells after the treatment of miR-20a-5p mimic. Meanwhile, the silencing of circPRKCI promoted the expression of miR-20a-5p in T-ALL cells, implying that circPRKCI serves as a competitive endogenous RNAs (ceRNA) of miR-20a-5p. We validated that the treatment of miR-20a-5p mimic inhibited the viability of T-ALL cells. MiR-20a-5p mimic enhanced the apoptosis of T-ALL cells. The expression of cleaved PARP and cleaved caspase3 was increased by miR-20a-5p mimic in the cells. In summarization, we concluded that circular RNA circPRKCI contributed to malignant progression of T-cell acute lymphoblastic leukemia by modulating miR-20a-5p/SOX4 axis. Targeting circPRKCI may serve as a promising therapeutic strategy of T-ALL.

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Hypoxic tubular epithelial cells regulate the angiogenesis of HMEC-1 cells via mediation of Rab7/MMP-2 axis

Yiqiong Yang1 , Jing Wang2 , Yu Zhang1 , Xiuxiu Hu1 , Li Li1 , Pingsheng Chen3

doi : 10.18632/aging.203648

Volume 13, Issue 20 pp 23769—23779

Renal hypoxia is associated with persisting peritubular capillary rarefaction in progression of chronic kidney disease (CKD), and this phenomenon mainly resulted from the dysregulated angiogenesis. Rab7 is known to be involved in renal hypoxia. However, the mechanism by which Rab7 regulates the renal hypoxia remains unclear. Protein expression was detected by western blot. Cell proliferation was detected by EdU staining. Cell migration was tested by transwell assay. Rab7 was upregulated in HK-2 cells under hypoxia conditions. Hypoxia significantly inhibited the viability and proliferation of human microvascular endothelial cells (HMEC-1 cells), while this phenomenon was obviously reversed by Rab7 silencing. Consistently, Hypoxia significantly decreased the migration and tube length of HMECs, which was partially reversed by knockdown of Rab7. Moreover, hypoxia-induced inhibition of MMP2 activity was significantly rescued by knockdown of Rab7. Moreover, ARP100 (MMP-2 inhibitor) significantly reversed the effect of Rab7 shRNA on cell viability, migration and angiogenesis. Furthermore, knockdown of Rab7 significantly alleviated the fibrosis in tissues of mice. Knockdown of Rab7 significantly alleviated the renal hypoxia in chronic kidney disease through regulation of MMP-2. Thus, our study might shed new light on exploring the new strategies against CKD.

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Matairesinol exerts anti-inflammatory and antioxidant effects in sepsis-mediated brain injury by repressing the MAPK and NF-?B pathways through up-regulating AMPK

Qin Wu1 , Yuhua Wang1 , Qingfang Li1

doi : 10.18632/aging.203649

Volume 13, Issue 20 pp 23780—23795

Brain injury is a familiar complication of severe sepsis, in which excessive inflammation and oxidative stress are the main mechanisms leading to acute brain injury. Here, we focus on probing the function and mechanism of Matairesinol (Mat) in sepsis-mediated brain injury. We established a rat sepsis model by cecal ligation and perforation (CLP) and constructed an in vitro sepsis model by treating neurons and microglia with lipopolysaccharide (LPS). Rats and cells were treated with varying concentrations of Mat, and the changes of neural function, neuronal apoptosis, microglial activation, neuroinflammation and the expression of oxidative stress factors in brain tissues were examined. Additionally, the activation of the MAPK, NF-?B and AMPK pathways in brain tissues and cells was evaluated by Western blot (WB) and/or immunohistochemistry (IHC). Our findings illustrated that Mat improved neuronal apoptosis and weakened microglial activation in CLP rats. Meanwhile, Mat hampered the expression of pro-inflammatory factors (TNF-?, IL-1?, IL-6, IFN-?, IL-8, and MCP1) and facilitated the contents of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in brain tissues and microglia. Mechanistically, Mat concentration-dependently dampened the phosphorylation of MAPK, JNK and NF-?B in CLP rats and LPS-stimulated microglia and up-regulated Nrf2 and HO-1. Besides, Mat facilitated the AMPK expression. Meanwhile, Compound C, a specific inhibitor of the AMPK pathway, substantially reduced the neuronal protection and anti-inflammatory effects mediated by Mat. Overall, Mat exerts anti-inflammatory and anti-oxidative stress effects by up-regulating AMPK, thereby ameliorating sepsis-mediated brain injury.

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Clinicopathological and prognostic value of long noncoding RNA SNHG7 in cancers: a meta-analysis and bioinformatics

June Wang1, * , Shenlin Du3, * , Chen Wang4, * , Zinian Zhu3 , Baocheng Xie2 , Bashan Zhang3, &

doi : 10.18632/aging.203650

Volume 13, Issue 20 pp 23796—23809

The long intergenic non-coding RNA SNHG7 has been reported to be abnormally expressed in many types of cancer, the results remain controversial. In this study, a meta-analysis was performed to evaluate the clinicopathologic and prognostic value of SNHG7 in cancers. Electronic databases of PubMed, Web of Science, Cochrane Library and Embase were used to search relevant studies. A combined hazard ratio (HR) and its corresponding 95% confidence interval (CI) were used to assess the association between SNHG7 expression and prognosis in cancer patients. Pooled odds ratio (OR) and 95% CI were calculated to elaborate the association between SNHG7 expression and clinicopathological features in cancers. Besides, the data from The Cancer Genome Atlas (TCGA) dataset was used to validate the results. In total, eighteen studies compromising 1303 participants were enrolled in this analysis. The pooled results showed increased SNHG7 expression could predict unfavorable overall survival (OS) (HR = 1.75, 95%CI = 1.52–2.02, P = 0.000). Analysis stratified by follow-up time, cancer types, analysis types, sample sizes and cut off further verified the prognostic value of SNHG7. Additionally, elevated SNHG7 expression was correlated with TNM stage (OR: 3.31, 95%CI = 2.29–4.80, P = 0.000), lymph node metastasis (OR = 3.32, 95%CI = 1.61–6.83, P = 0.004), and tumor differentiation (OR = 1.92, 95%CI = 1.22–3.03, P =0.005) in patients with cancers. Excavation of TCGA dataset valuated that SNHG7 was upregulated in some cancers and predicted worse OS, which partially confirmed our results in this meta-analysis.

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CCR5 is a prognostic biomarker and an immune regulator for triple negative breast cancer

Xin Wang1, * , Yong Han2,3, * , Jiamin Peng4 , Jie He1

doi : 10.18632/aging.203654

Volume 13, Issue 20 pp 23810—23830

This study aims to explore the clinical implications and potential mechanistic functions of CCR5 in triple negative breast cancer. Briefly, we demonstrated that CCR5 is overexpressed in TNBC and is associated with better prognosis of TNBC. CCR5 expression is positively correlated with tumor immune cell infiltration and tumor immune response related pathways. Multi-omics data analyses identified CCR5 associated genomic and proteomic changes. CCR5 overexpression was associated with better overall survival in TNBC patients with TP53 mutation. We also summarized the latest findings on ICB efficacy related genes and explored the association between CCR5 and those genes. These results indicated that CCR5 is a potential tumor suppressor gene and individualized therapeutic strategy could be established based on multi-omics background and expression pattern of ICB related genes. In conclusion, CCR5 is associated with better survival of TNBC patients with TP53 mutation, which may exert its roles through tumor immune environment.

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CircFAM120B knockdown inhibits osteosarcoma tumorigenesis via the miR-1205/PTBP1 axis

Jia-Ju Li1 , Ming-Yue Xiong1 , Tian-Yu Sun1 , Chang-Bin Ji1 , Run-Tao Guo1 , Ya-Wei Li2 , Hong-Yu Guo1

doi : 10.18632/aging.203657

Volume 13, Issue 20 pp 23831—23841

Osteosarcoma (OS) is a highly prevalent bone malignancy with poor clinical outcomes. Expression of the circular RNA, hsa_circ_0078767 (circFAM120B) is elevated in OS, however, its mechanisms in OS are unclear.

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Differential expression of long non-coding RNAs as diagnostic markers for lung cancer and other malignant tumors

Li Li1,2, * , Haitao Wei2,3, * , Yi Wei Zhang1 , Shizhe Zhao4 , Guowei Che2 , Yun Wang2 , Longqi Chen2

doi : 10.18632/aging.203523

Volume 13, Issue 20 pp 23842—23867

Due to advances in chip and sequencing technology, several types and numbers of long non-coding RNAs (lncRNAs) have been identified. LncRNAs are defined as non-protein-coding RNA molecules longer than 200 nucleotides, and are now thought as a new frontier in the study of human malignant diseases including NSCLC. Diagnosis of numerous malignant tumors has been closely linked to the differential expression of certain lncRNAs. LncRNAs are involved in gene expression regulation at multiple levels of epigenetics, transcriptional regulation, and post-transcriptional regulation. Mutations, deletions, or abnormal expression levels lead to physiological abnormalities, disease occurrence and are closely associated with human tumor diseases. LncRNAs play a crucial role in cancerous processes as either oncogenes or tumor suppressor genes. The expression of lncRNAs can regulate tumor cell in the proliferation, migration, apoptosis, cycle, invasion, and metastasis. As such, lncRNAs are potential diagnostic and treatment targets for cancer. And that, tumor biomarkers need to be detectable in easily accessible body samples, should be characterized by high specificity and sufficient sensitivity. Herein, it is significant clinical importance to screen and supplement new biomarkers for early diagnosis of lung cancer. This study aimed at systematically describing lncRNAs from five aspects based on recent studies: concepts, classification, structure, molecular mechanism, signal pathway, as well as review lncRNA implications in malignant tumor.

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Correction for: CircRNA_100367 regulated the radiation sensitivity of esophageal squamous cell carcinomas through miR-217/Wnt3 pathway

Junqi Liu1 , Nannan Xue1 , Yuexin Guo1 , Kerun Niu2 , Liang Gao3 , Song Zhang1 , Hao Gu1 , Xin Wang1 , Di Zhao4 , Ruitai Fan1

doi : 10.18632/aging.203664

Volume 13, Issue 20 pp 23868—23870

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Correction for: YKL40 in sporadic amyotrophic lateral sclerosis: cerebrospinal fluid levels as a prognosis marker of disease progression

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doi : 10.18632/aging.203667

Volume 13, Issue 20 pp 23871

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