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Killifish switch towards mammalian-like regeneration upon aging
Sophie Vanhunsel, Steven Bergmans, Lieve Moons
doi : 10.18632/aging.203995
pp 2924—2925
Dopaminergic neurons: linking longevity with reproduction?
Xiaolin Tian
doi : 10.18632/aging.204000
pp 2926—2927
MicroRNAs in aging male reproduction
Lu Zheng, Jinzhao Ma, Bing Yao
doi : 10.18632/aging.204003
pp 2928—2929
Association between sleep parameters and longitudinal shortening of telomere length
Jeong-Hwa Jin1, * , Hyuk Sung Kwon1, * , Seong Hye Choi2 , Seong-Ho Koh1 , Eun-Hye Lee1 , Jee Hyang Jeong3 , Jae-Won Jang4 , Kyung Won Park5 , Eun-Joo Kim6 , Hee Jin Kim7 , Jin Yong Hong8 , Soo Jin Yoon9 , Bora Yoon10 , Hyun-Hee Park1 , Jungsoon Ha1,11 , Jong Eun Park12 , Myung Hoon Han13
doi : 10.18632/aging.203993
Volume 14, Issue 7 pp 2930—2944
Background: The relationship between sleep parameters and longitudinal shortening of telomere length is unclear. This study aimed to investigate the relationship between sleep parameters and the shortening of leukocyte telomere length (LTL) over a year.
E-cadherin deficiency promotes prostate macrophage inflammation and bladder overactivity in aged male mice
Laura E. Pascal1,2,3 , Taro Igarashi1 , Shinsuke Mizoguchi1 , Wei Chen1 , Lora H. Rigatti4 , Caroline G. Madigan2 , Rajiv Dhir5 , Wade Bushman6 , Donald B. DeFranco2,7 , Naoki Yoshimura1 , Zhou Wang1,2,3
doi : 10.18632/aging.203994
Volume 14, Issue 7 pp 2945—2965
Decreased E-cadherin immunostaining is frequently observed in benign prostatic hyperplasia (BPH) and was recently correlated with increased inflammation in aging prostate. Homozygous E-cadherin deletion in the murine prostate results in prostate inflammation and bladder overactivity at 6 months of age. However, this model is limited in that while E-cadherin is significantly reduced in BPH, it is not completely lost; BPH is also strongly associated with advanced age and is infrequent in young men. Here, we examined the functional consequences of aging in male mice with prostate luminal epithelial cell-specific E-cadherin heterozygosity. In control mice, aging alone resulted in an increase in prostate inflammation and changes in bladder voiding function indicative of bladder underactivity. At 24 months of age, mice with prostate-specific Cre-mediated heterozygous deletion of E-cadherin induced at 7 weeks of age developed additional prostatic defects, particularly increased macrophage inflammation and stromal proliferation, and bladder overactivity compared to age-matched control mice, which are similar to BPH/LUTS in that the phenotype is slow-progressing and age-dependent. These findings suggest that decreased E-cadherin may promote macrophage inflammation and fibrosis in the prostate and subsequent bladder overactivity in aging men, promoting the development and progression of BPH/LUTS.
Downregulation of IGFBP5 contributes to replicative senescence via ERK2 activation in mouse embryonic fibroblasts
Iyori Nojima1 , Ryusuke Hosoda1 , Yuki Toda1 , Yoshiki Saito1 , Naohiro Ueda1 , Kouhei Horimoto1 , Naotoshi Iwahara1 , Yoshiyuki Horio1 , Atsushi Kuno1
doi : 10.18632/aging.203999
Volume 14, Issue 7 pp 2966—2988
Insulin-like growth factor (IGF)-binding proteins (IGFBPs) are secretory proteins that regulate IGF signaling. In this study, we investigated the role of IGFBP5 in replicative senescence in embryonic mouse fibroblasts (MEFs). During passages according to the 3T3 method, MEFs underwent senescence after the 5th passage (P5) based on cell growth arrest, an increase in the number of cells positive for senescence-associated β-galactosidase (SA-β-GAL) staining, and upregulation of p16 and p19. In P8 MEFs, IGFBP5 mRNA level was markedly reduced compared with that in P2 MEFs. Downregulation of IGFBP5 via siRNA in P2 MEFs increased the number of SA-β-GAL-positive cells, upregulated p16 and p19, and inhibited cell growth. Incubation of MEFs with IGFBP5 during serial passage increased the cumulative population doubling and decreased SA-β-GAL positivity compared with those in vehicle-treated cells. IGFBP5 knockdown in P2 MEFs increased phosphorylation levels of ERK1 and ERK2. Silencing of ERK2, but not that of ERK1, blocked the increase in the number of SA-β-GAL-positive cells in IGFBP5-knockdown cells. The reduction in the cell number and upregulation of p16 and p21 in IGFBP5-knockdown cells were attenuated by ERK2 knockdown. Our results suggest that downregulation of IGFBP5 during serial passage contributes to replicative senescence via ERK2 in MEFs.
The tobacco phosphatidylethanolamine-binding protein NtFT4 increases the lifespan of Drosophila melanogaster by interacting with the proteostasis network
Philip Känel1 , Gundula A. Noll2 , Katrin Schroedter1 , Elke Naffin3 , Julia Kronenberg1 , Franziska Busswinkel1 , Richard M. Twyman4 , Christian Klämbt3 , Dirk Prüfer1,2
doi : 10.18632/aging.204005
Volume 14, Issue 7 pp 2989—3029
Proteostasis reflects the well-balanced synthesis, trafficking and degradation of cellular proteins. This is a fundamental aspect of the dynamic cellular proteome, which integrates multiple signaling pathways, but it becomes increasingly error-prone during aging. Phosphatidylethanolamine-binding proteins (PEBPs) are highly conserved regulators of signaling networks and could therefore affect aging-related processes. To test this hypothesis, we expressed PEPBs in a heterologous context to determine their ectopic activity. We found that heterologous expression of the tobacco (Nicotiana tabacum) PEBP NtFT4 in Drosophila melanogaster significantly increased the lifespan of adult flies and reduced age-related locomotor decline. Similarly, overexpression of the Drosophila ortholog CG7054 increased longevity, whereas its suppression by RNA interference had the opposite effect. In tobacco, NtFT4 acts as a floral regulator by integrating environmental and intrinsic stimuli to promote the transition to reproductive growth. In Drosophila, NtFT4 engaged distinct targets related to proteostasis, such as HSP26. In older flies, it also prolonged Hsp26 gene expression, which promotes longevity by maintaining protein integrity. In NtFT4-transgenic flies, we identified deregulated genes encoding proteases that may contribute to proteome stability at equilibrium. Our results demonstrate that the expression of NtFT4 influences multiple aspects of the proteome maintenance system via both physical interactions and transcriptional regulation, potentially explaining the aging-related phenotypes we observed.
Skin cutaneous melanoma properties of immune-related lncRNAs identifying potential prognostic biomarkers
Yutong Ma3 , Ning Wang1 , Shude Yang1,2
doi : 10.18632/aging.203982
Volume 14, Issue 7 pp 3030—3048
Skin cutaneous melanoma (SKCM) is one of the most aggressive and life-threatening cancers with high incidence rate, metastasis rate and mortality. Early detection and stratification of risk assessment are essential to treat SKCM and to improve survival rate. The aim of this study is to construct an immune-related lncRNAs (immlncRNAs) prognosis risk model to identify immune biomarkers for early diagnosis, prognosis assessment and target immunotherapy of SKCM. For this purpose, we identified 46 immlncRNAs significantly correlated with SKCM prognosis to construct the prognostic risk model and patients were stratified into the high- and low-risk subgroups according to the developed model. The predictive efficiency of this model has been proved by K-M survival analysis and receiver operating characteristic curve. Moreover, CIBERSORT algorithms confirmed that there were differences in immune cell infiltration between the high- and low-risk groups. Functional enrichment analysis further indicated that immlncRNAs were related to a variety of immune response process signaling pathways, suggesting that relevant immlncRNAs could play an important role in the immune regulation of SKCM. Finally, subgroup analysis and multiple Cox regression analysis further proved the stability of the model. In summary, we successfully constructed a 46 immlncRNA-related prognostic risk score model with excellent predictive efficacy and provided more possibilities to investigate the immune regulation mechanisms and to develop immunotherapy of SKCM.
Circular RNA circGSE1 promotes angiogenesis in ageing mice by targeting the miR-323-5p/NRP1 axis
Jiacong Qiu1,2,3 , Rencong Chen1,2,3 , Lei Zhao1,2,3 , Chong Lian4 , Zhen Liu1,2,3 , Xiaonan Zhu5 , Jin Cui1,2,3 , Siwen Wang1,2,3 , Mingshan Wang1,2,3 , Yingxiong Huang6 , Shenming Wang1,2,3 , Jinsong Wang1,2,3
doi : 10.18632/aging.203988
Volume 14, Issue 7 pp 3049—3069
Age is an important factor in many cardiovascular diseases, in which endothelial cells (ECs) play an important role. Circular RNAs (circRNAs) have been reported in many cardiovascular diseases, but their role in ageing EC-related angiogenesis is unclear. We aimed to identify a functional circRNA that regulates angiogenesis during ageing and explore its specific mechanism. In this study, we searched for differentially expressed circRNAs in old endothelial cells (OECs) and young endothelial cells (YECs) by circRNA sequencing and found that circGSE1 was significantly downregulated in OECs. Our study showed that circGSE1 could promote the proliferation, migration and tube formation of OECs in vitro. In a mouse model of femoral artery ligation and ischemia, circGSE1 promoted blood flow recovery and angiogenesis in the ischemic limbs of ageing mice. Mechanistically, we found that overexpressing circGSE1 reduced miR-323-5p expression, increased neuropilin-1 (NRP1) expression, and promoted proliferation, migration, and tube formation in OECs, while knocking down circGSE1 increased miR-323-5p expression, reduced NRP1 expression, and inhibited proliferation, migration, and tube formation in YECs. During EC ageing, circGSE1 may act through the miR-323-5p/NRP1 axis and promote endothelial angiogenesis in mice. Finally, the circGSE1/miR-323-5p/NRP1 axis could serve as a potential and promising therapeutic target for angiogenesis during ageing.
Hypoxic pretreatment of adipose-derived stem cell exosomes improved cognition by delivery of circ-Epc1 and shifting microglial M1/M2 polarization in an Alzheimer’s disease mice model
Haining Liu1,2, * , Mingming Jin3, * , Minxiu Ji1,2 , Wei Zhang1,2 , An Liu1,2 , Tao Wang1,2
doi : 10.18632/aging.203989
Volume 14, Issue 7 pp 3070—3083
Alzheimer’s disease (AD) is the most common dementia in the world. Increasing evidence has shown that exosomes from hypoxic pretreated adipose-derived stem cells (ADSCs) could be an effective cognitive function therapeutic in AD-associated pathophysiology. However, their role and regulatory mechanism remain largely unknown. High-throughput sequencing was used to identify differentially expressed circRNAs from ADSCs or hypoxia pretreated ADSC exosomes. Luciferase reporter assays and RT-qPCR were used to investigate the relationships between circ-Epc1, miR-770-3p, and TREM2. APP/PS1 double transgenic AD model mice were then used to study therapeutic effects regarding circ-Epc1 in ADSC exosomes. BV2 cells were used to show the regulatory relationships between circ-Epc1, miR-770-3p, and TREM2 and to show how these interactions modulated phenotypic transformations and inflammatory cytokine expressions in microglia. The results showed that exosomes from hypoxia pretreated ADSCs had a good therapeutic effect on improving cognitive functions by decreasing neuronal damage in the hippocampus. High-throughput sequencing showed that circ-Epc1 played an important role in hypoxia-pretreated ADSC exosomes regarding their ability to improve cognitive functions. Luciferase reporter assays showed that TREM2 and miR-770-3p were downstream targets of circ-Epc1. Overexpressing miR-770-3p or downregulating TREM2 reversed the effects of circ-Epc1 on M2 microglia during lipopolysaccharide treatment. In vivo experiments showed that circ-Epc1-containing ADSC exosomes increased the therapeutic effect of exosomes by improving cognitive function, decreasing neuronal damage, and shifting hippocampal microglia from the M1 polarization to the M2 polarization stages. Taken together, the data show that hypoxic pretreatment of ADSC exosomes improved cognition by delivery of circ-Epc1 and by shifting microglial M1/M2 polarization in an AD mouse model.
Mechanisms of action of triptolide against colorectal cancer: insights from proteomic and phosphoproteomic analyses
Xinqiang Song1,2 , Huanhuan He1 , Yu Zhang1 , Jinke Fan1 , Lei Wang1
doi : 10.18632/aging.203992
Volume 14, Issue 7 pp 3084—3104
Triptolide is a potent anti-inflammatory agent that also possesses anticancer activity, including against colorectal cancer (CRC), one of the most frequent cancers around the world. In order to clarify how triptolide may be effective against CRC, we analyzed the proteome and phosphoproteome of CRC cell line HCT116 after incubation for 48 h with the drug (40 nM) or vehicle. Tandem mass tagging led to the identification of 403 proteins whose levels increased and 559 whose levels decreased in the presence of triptolide. We also identified 3,110 sites in proteins that were phosphorylated at higher levels and 3,161 sites phosphorylated at lower levels in the presence of the drug. Analysis of these differentially expressed and/or phosphorylated proteins showed that they were enriched in pathways involving ribosome biogenesis, PI3K−Akt signaling, MAPK signaling, nucleic acid binding as well as other pathways. Protein–protein interactions were explored using the STRING database, and we identified nine protein modules and 15 hub proteins. Finally, we identified 57 motifs using motif analysis of phosphosites and found 16 motifs were experimentally verified for known protein kinases, while 41 appear to be novel. These findings may help clarify how triptolide works against CRC and may guide the development of novel treatments.
Circular RNA_0006014 promotes breast cancer progression through sponging miR-885-3p to regulate NTRK2 and PIK3/AKT pathway
Xiqian Zhou1, * , Wei Jian1, * , Qifeng Luo1 , Wenfang Zheng1 , Xiaochong Deng1 , Xuehui Wang1 , Oyungerel Borkhuu1 , Changle Ji1 , Dengfeng Li1 , Lin Fang1
doi : 10.18632/aging.203996
Volume 14, Issue 7 pp 3105—3128
Breast cancer is the most common cancer in women worldwide. Numerous reports have demonstrated that circRNAs play an essential role in regulating the biological characteristics of breast cancer. However, there are currently no reports regarding the role of hsa_circ_0006014 in breast cancer. In this study, qRT-PCR was used to detect the expression of hsa_circ_0006014 and related genes. MTT, colony formation and Transwell assays were used to explore the potential biological functions of hsa_circ_0006014 in breast cancer cells. Western blotting was used to explore the potential molecular mechanisms involving hsa_circ_0006014. In vivo experiments were used to evaluate the influence of hsa_circ_0006014 on animal tumors. In this study, we found higher expression of hsa_circ_0006014 in breast tumor samples than in matched adjacent normal samples, and its expression was positively correlated with histological grade (grade iii). Phenotypically, hsa_circ_0006014 promoted the proliferation of MDA-MB-231 and MCF-7 breast cancer cells. Mechanistically, there were confirmed binding sites between hsa_circ_0006014 and miR-885-3p, and hsa_circ_0006014 promoted breast cancer cell proliferation partially by sponging miR-885-3p and influenced CDK2/CCNE1 and CDK4/6/CCND1. Furthermore, we found that hsa_circ_0006014 regulated NTRK2 through miR-885-3p to modulate the PIK3/AKT signaling pathway. Our results demonstrated that hsa_circ_0006014 promotes breast cancer progression by sponging miR-885-3p to regulate the NTRK2/PIK3CA/AKT axis.
miRNA-29 aggravates myocardial infarction via inhibiting the PI3K/mTOR/HIF1α/VEGF pathway
Xiaoxi Wang1 , Yanning Liu2 , Huiqing Hou3 , Weihua Shao4 , Dai Huang5 , Zhihua Hao3 , Hongyuan Xue5 , Yuquan Ye6
doi : 10.18632/aging.203997
Volume 14, Issue 7 pp 3129—3142
Introduction: MI is defined by the presence of myocardial necrosis, which is caused by acute and persistent ischemia and hypoxia of the coronary artery. In recent years, its incidence rate has been on the rise in China.
Elevated lncRNA MIAT in peripheral blood mononuclear cells contributes to post-menopausal osteoporosis
Rui Li1 , Ting-Ting Shi2 , Qiang Wang2 , Yong-Xian Zhang1
doi : 10.18632/aging.204001
Volume 14, Issue 7 pp 3143—3154
Inflammatory cytokines contribute to the development of osteoporosis with sophisticated mechanisms. Globally alteration of long-chain non-coding RNA was screened in osteoporosis, while we still know little about their functional role in the inflammatory cytokine secretion. In this study, we collected the peripheral blood mononuclear cells (PBMCs) from post-menopausal osteoporosis patients to measure lncRNA MIAT (lncMIAT) expression levels, and explored the molecular mechanism of lncMIAT induced inflammatory cytokine secretion. We identified increased lncMIAT expression in the PBMCs of post-menopausal osteoporosis patients, which was an important predictive biomarker for the diagnosis. LncMIAT expression in PBMCs was positively correlated with the inflammatory cytokine secretion. Mechanism study indicated that lncMIAT increased the expression levels of p38MAPK by crosstalk with miR-216a in PBMCs. The lncMIAT/miR-216a/p38MAPK signaling contributed predominantly to the increased inflammatory cytokine secretion in the PBMCs from postmenopausal osteoporosis. In conclusion, we identified that increased lncMIAT in PBMCs induced inflammatory cytokine secretion, which contributed to the development of post-menopausal osteoporosis. lncMIAT/miR-216a axis was critical for the regulation of AMPK/p38MAPK signaling, which may be a promising therapeutic target for osteoporosis treatment by inflammatory cytokine inhibition.
A novel classification method for NSCLC based on the background interaction network and the edge-perturbation matrix
Yuan Tian1, * , Caiqing Zhang2, * , Wanru Ma3, * , Alan Huang4 , Mei Tian5 , Junyan Zhao6 , Qi Dang7 , Yuping Sun7
doi : 10.18632/aging.204004
Volume 14, Issue 7 pp 3155—3174
The biological functional network of tumor tissues is relatively stable for a period of time and under different conditions, so the impact of tumor heterogeneity is effectively avoided. Based on edge perturbation, functional gene interaction networks were used to reveal the pathological environment of patients with non-small cell carcinoma at the individual level, and to identify cancer subtypes with the same or similar status, and then a multi-dimensional and multi-omics comprehensive analysis was put into practice. Two edge perturbation subtypes were identified through the construction of the background interaction network and the edge-perturbation matrix (EPM). Further analyses revealed clear differences between those two clusters in terms of prognostic survival, stemness indices, immune cell infiltration, immune checkpoint molecular expression, copy number alterations, mutation load, homologous recombination defects (HRD), neoantigen load, and chromosomal instability. Additionally, a risk prediction model based on TCGA for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) was successfully constructed and validated using the independent data set (GSE50081).
Burden of lymphoma in China, 1990−2019: an analysis of the global burden of diseases, injuries, and risk factors study 2019
Weiping Liu1, * , Jiangmei Liu2, * , Yuqin Song1 , Xiaopei Wang1 , Lan Mi1 , Cai Cai3 , Donglu Zhao4 , Lijun Wang2 , Jun Ma4 , Jun Zhu1
doi : 10.18632/aging.204006
Volume 14, Issue 7 pp 3175—3190
Background: China is facing an aggravating disease burden of lymphoma. However, accurate information about lymphoma burden at the national and provincial levels is limited.
Epitalon protects against post-ovulatory aging-related damage of mouse oocytes in vitro
Xue Yue1,2,3 , Sai-Li Liu3 , Jia-Ni Guo3 , Tie-Gang Meng3 , Xin-Ran Zhang3 , Hong-Xia Li2 , Chun-Ying Song2 , Zhen-Bo Wang3 , Heide Schatten4 , Qing-Yuan Sun5 , Xing-Ping Guo1,2
doi : 10.18632/aging.204007
Volume 14, Issue 7 pp 3191—3202
The developmental potential of oocytes decreases with time after ovulation in vivo or in vitro. Epitalon is a synthetic short peptide made of four amino acids (alanine, glutamic acid, aspartic acid, and glycine), based on a natural peptide called epithalamion extracted from the pineal gland. It is a potent antioxidant, comparable to melatonin, that may confer longevity benefits. The current study aims to test the protective effects of Epitalon on the quality of post-ovulatory aging oocytes. Epitalon at 0.1mM was added to the culture medium, and the quality of oocytes was evaluated at 6h, 12h, and 24h of culture. We found that 0.1mM Epitalon reduced intracellular reactive oxygen species. Epitalon treatment significantly decreased frequency of spindle defects and abnormal distribution of cortical granules during aging for 12h and 24h, while increased mitochondrial membrane potential and DNA copy number of mitochondria, thus decreasing apoptosis of oocytes by 24h of in vitro aging. Our results suggest that Epitalon can delay the aging process of oocytes in vitro via modulating mitochondrial activity and ROS levels.
Survival and prognostic analysis of T-cell lymphoblastic lymphoma patients treated with dose-adjusted BFM-90 regimen
Hui Yu1 , Lan Mi1 , Fei Qi1 , Xing Wang1 , Yingying Ye1 , Miaomiao Li1 , Dedao Wang1 , Ning Ding1 , Xiaogan Wang1 , Yuqin Song1 , Jun Zhu1 , Yan Xie1
doi : 10.18632/aging.204008
Volume 14, Issue 7 pp 3203—3215
We aimed to investigate the long-term prognosis and prognostic factors of T-cell lymphoblastic lymphoma (T-LBL) patients who received dose-adjusted Berlin–Frankfurt–Münster (BFM)-90 regimen as first-line therapy in our center. A total of 145 T-LBL patients who underwent first-line dose-adjusted BFM-90 was retrospectively reviewed. Conditional survival analysis was used to evaluate the long-term prognosis of patients. Receiver operating characteristic (ROC) curve was applied to determine the optimal cut-off value for neutrophil-to-lymphocyte ratio (NLR). Estimated 3-year overall survival (OS) and progression-free survival (PFS) rates for overall were 66.8% and 58.4%, respectively. Conditional survival analysis showed that for patients having survived 3 and 5 years or more after the completion of the treatment, the estimated subsequent 3-year OS thereafter increased to 85.7% and 94.3, respectively. Patients receiving consolidation APBSCT (Autologous peripheral blood stem cell transplantation) after BFM-90 regimen had superior 3-year OS than those with non-APBSCT (79.1% vs. 33.4%, p<0.001). We also discovered that baseline NLR ≥4.95 was negatively associated with OS (HR=2.75, 95% CI 1.55-4.89, p=0.015) and PFS (HR=2.07, 95% CI 1.25-4.96, p=0.021) via multivariable analysis. Conclusions: The survival probability of T-LBL patients treated with first-line dose-adjusted BFM-90 has improved significantly as patients have survived for every additional year. The addition of consolidation APBSCT following dose-adjusted BFM-90 therapy bring further survival benefits for those patients. Baseline NLR ≥4.95 was an independent risk factor for T-LBL patients in our study.
Trehalose inhibits ferroptosis via NRF2/HO-1 pathway and promotes functional recovery in mice with spinal cord injury
Fangyi Gong1, * , Ting Ge1, * , Jing Liu2, * , Jin Xiao1 , Xiaochuan Wu1 , Hehui Wang1 , Yingchun Zhu1 , Dongdong Xia1 , Baiwen Hu1
doi : 10.18632/aging.204009
Volume 14, Issue 7 pp 3216—3232
Spinal cord injury (SCI) is the main cause of severe damage to the central nervous system and leads to irreversible tissue loss and neurological dysfunction. Ferroptosis is a cell death pattern, newly discovered in recent years. Ferroptosis is an oxidizing cell death induced by small molecules, and is an iron-dependent process caused by the imbalance between the generation and degradation of lipid reactive oxygen species (ROS) in cells. As an antioxidant, trehalose can effectively prevent lipid peroxidation. Studies have reported that trehalose can improve the prognosis of SCI. However, it is unclear whether these benefits are related to ferroptosis. In this study, we demonstrated for the first time that trehalose reduces the degeneration and iron accumulation of neurons by inhibiting the production of ROS and ferroptosis caused by lipid peroxides after SCI, thus promoting the survival of neurons and improving the recovery of motor function. More specifically, we found that trehalose inhibited the expansion of cavities in the nerve tissue of mice with SCI, inhibited neuron loss, and improved functional recovery. In terms of mechanism, our results indicate that the neuroprotective effect of trehalose is due to the activation of the NRF2/HO-1 pathway, which in turn inhibits ferroptosis and ferroptosis-related inflammation. Our findings provide important insights into the previously unknown role of trehalose in SCI, as well as new evidence supporting the hypothesis that suppression of ferroptosis plays a key neuroprotective role in SCI.
The role of fructose 1,6-bisphosphate-mediated glycolysis/gluconeogenesis genes in cancer prognosis
Chien-Hsiu Li1 , Ming-Hsien Chan1 , Yu-Chan Chang2
doi : 10.18632/aging.204010
Volume 14, Issue 7 pp 3233—3258
Metabolic reprogramming and elevated glycolysis levels are associated with tumor progression. However, despite cancer cells selectively inhibiting or expressing certain metabolic enzymes, it is unclear whether differences in gene profiles influence patient outcomes. Therefore, identifying the differences in enzyme action may facilitate discovery of gene ontology variations to characterize tumors. Fructose-1,6-bisphosphate (F-1,6-BP) is an important intermediate in glucose metabolism, particularly in cancer. Gluconeogenesis and glycolysis require fructose-1,6-bisphosphonates 1 (FBP1) and fructose-bisphosphate aldolase A (ALDOA), which participate in F-1,6-BP conversion. Increased expression of ALDOA and decreased expression of FBP1 are associated with the progression of various forms of cancer in humans. However, the exact molecular mechanism by which ALDOA and FBP1 are involved in the switching of F-1,6-BP is not yet known. As a result of their pancancer pattern, the relationship between ALDOA and FBP1 in patient prognosis is reversed, particularly in lung adenocarcinoma (LUAD) and liver hepatocellular carcinoma (LIHC). Using The Cancer Genome Atlas (TCGA), we observed that FBP1 expression was low in patients with LUAD and LIHC tumors, which was distinct from ALDOA. A similar trend was observed in the analysis of Cancer Cell Line Encyclopedia (CCLE) datasets. By dissecting downstream networks and possible upstream regulators, using ALDOA and FBP1 as the core, we identified common signatures and interaction events regulated by ALDOA and FBP1. Notably, the identified effectors dominated by ALDOA or FBP1 were distributed in opposite patterns and can be considered independent prognostic indicators for patients with LUAD and LIHC. Therefore, uncovering the effectors between ALDOA and FBP1 will lead to novel therapeutic strategies for cancer patients.
Cholesterol-induced leucine aminopeptidase 3 (LAP3) upregulation inhibits cell autophagy in pathogenesis of NAFLD
Lina Feng1,2, * , Yanping Chen3,4, * , Ke Xu5 , Yingchao Li6 , Farooq Riaz1,2 , Kaikai Lu1,2 , Qian Chen1,2 , Xiaojuan Du1,2 , Litao Wu1,2 , Dan Cao4 , Chunyan Li3 , Shemin Lu1,2 , Dongmin Li1,2
doi : 10.18632/aging.204011
Volume 14, Issue 7 pp 3259—3275
Objectives: Leucine aminopeptidase 3 (LAP3), an M1 member of leucine aminopeptidase, was reported to be significantly upregulated in serum of nonalcoholic fatty liver disease (NAFLD) patients. However, the underlying mechanisms of LAP3 in NAFLD pathogenesis are still unknown. We aim to investigate the role of LAP3 in NAFLD pathogenesis and explore whether LAP3 has the potential to be a candidate biomarker in serum for NAFLD diagnosis.
An immune subtype-related prognostic signature of hepatocellular carcinoma based on single-cell sequencing analysis
Jiaheng Xie1, * , Liang Chen2, * , Qingmei Sun3, * , Haobo Li4, * , Wei Wei2 , Dan Wu5 , Yiming Hu6 , Zhechen Zhu1 , Jingping Shi1, & , Ming Wang1
doi : 10.18632/aging.204012
Volume 14, Issue 7 pp 3276—3292
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world and is often associated with a poor prognosis. The main reason for this poor prognosis is that inconspicuous early symptoms lead to delayed diagnosis. Treatment options for advanced HCC remain limited and ineffective. In this context, the exploration of the immune microenvironment in HCC becomes attractive. In this study, we divided HCC into immune cell and non-immune cell subtypes, by single-cell sequencing analysis of GEO dataset GSE146115. We found differentially expressed genes in the two subtypes, which we used to construct a prognostic model for HCC through Cox and Lasso regressions. Our prognostic model can accurately evaluate the prognosis of HCC patients, and provide a reference for the design of immunotherapy for HCC.
Abnormal phenotype of Nrf2 is associated with poor prognosis through hypoxic/VEGF-A-Rap1b/VEGFR2 pathway in gastric cancer
Ya Yang1 , Xin Wang1 , Jia Zhang2 , Hao Gu1 , Song Zhang1 , Hao Sun1 , Junqi Liu1 , Ruitai Fan1
doi : 10.18632/aging.204013
Volume 14, Issue 7 pp 3293—3312
Metastasis is the major cause of death in gastric cancer patients and altered expression of Nrf2 is associated with cancer development. This study assessed Nrf2 and HO-1 expression and hypoxia-induced Nrf2 expression in the promotion of metastatic potential of gastric cancer cells, the relationship of Rap1b and Nrf2 was also discussed. Nrf2 and HO-1 expression were significantly associated with clinicopathological characteristic and were independent prognostic predictors in gastric cancer patients. Hypoxia up-regulated the expression of Nrf2, HO-1 and HIF-1α, whereas knockdown of Nrf2 inhibited cell invasion capacity and reduced the expression of Nrf2, HO-1 and HIF-1α. Patients in the Rap1b (+) Nrf2 (+) group had worst overall survival compared with those from other groups. Knockdown of Rap1b and Nrf2 significantly inhibited cell invasion capacity in the common group compared with the other groups. Hypoxia or VEGF-A facilitated the nuclear translocation of Nrf2 through Rap1b or VEGFR2. Hypoxia or VEGF-A did not induce the phosphorylation of P-Erk1/2 and P-Akt after knockdown of Rap1b or VEGFR2. Hypoxia promoted the gastric cancer malignant behavior through the upregulation of Rap1b and Nrf2. Hypoxia/VEGF-A-Rap1b/VEGFR2 facilitated the nuclear translocation of Nrf2. Targeting Rap1b and Nrf2 may be a novel therapeutic strategy for gastric cancer.
SNP rs322931 (C>T) in miR-181b and rs7158663 (G>A) in MEG3 aggravate the inflammatory response of anal abscess in patients with Crohn’s disease
Chaoxiang Zhong1 , Qiuju Yao1 , Jing Han1 , Jie Yang1 , Fei Jiang1 , Qiong Zhang1 , Haiyi Zhou1 , Yuchao Hu1 , Wei Wang1 , Yan Zhang1 , Ye Sun1
doi : 10.18632/aging.204014
Volume 14, Issue 7 pp 3313—3324
Background: The MEG3/miR-181b signaling has been implicated in the pathogenesis of several diseases including Crohn’s disease. This work aimed to study the correlation between SNPs in MEG3/miR-181b and the severity of anal abscess in patients with Crohn’s disease.
Heterochronic parabiosis: a valuable tool to investigate cellular senescence and other hallmarks of aging
Matthew J. Yousefzadeh1 , Paul D. Robbins1 , Derek M. Huffman2,3
doi : 10.18632/aging.204015
Volume 14, Issue 7 pp 3325—3328
Parabiosis is a well-established method to facilitate a shared blood supply between two conjoined animals. In particular, the pairing of mice of dissimilar ages, termed heterochronic parabiosis, has been used extensively for differentiating cell autonomous and non-autonomous mechanisms of aging. Analysis of heterochronic parabionts also has helped to identify individual circulating factors that may act as either pro- or anti-geronics. Heterochronic parabiosis also has proven to be a valuable experimental system to evaluate the effects of specific hallmarks of aging on the process of aging. For example, heterochronic parabiosis was used recently to examine whether cellular senescence was driven via cell autonomous and/or non-autonomous mechanisms. As anticipated, markers of cellular senescence were elevated in old isochronically-paired mice relative to young controls. However, compared to old isochronically paired mice, the senescent cell burden was reduced in multiple tissues of old parabionts joined with young mice. This suggests that the rejuvenation of cells and tissues in old mice by exposure to young blood could be mediated, in part, through suppression or immune clearance of senescent cells. Conversely, young heterochronic parabionts showed increased markers of cellular senescence, demonstrating that exposure to an old circulation is able to drive senescence through a cell non-autonomous mechanism(s), likely contributing to accelerated aging in the young mice. Thus, heterochronic parabiosis is still an important methodology that should continue to be leveraged for evaluating other hallmarks of aging and their mechanisms.
Correction for: Inhibition of CDK9 attenuates atherosclerosis by inhibiting inflammation and phenotypic switching of vascular smooth muscle cells
Shushi Huang1,2, * , Wu Luo1,3, * , Gaojun Wu2 , Qirui Shen1 , Zaishou Zhuang3 , Daona Yang3 , Jinfu Qian1 , Xiang Hu4 , Yan Cai3 , Nipon Chattipakorn5 , Weijian Huang2 , Guang Liang1,3,6
doi : 10.18632/aging.204017
Volume 14, Issue 7 pp 3329—3330
