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Targeting proteostasis maintenance and autophagy in senescence
Valentin L’Hôte, Carl Mann, Jean-Yves Thuret
doi : 10.18632/aging.203941
pp 2016—2017
Sex matters in Alzheimer’s disease?
Sheeja Navakkode, Toh Hean Ch’ng, Sreedharan Sajikumar
doi : 10.18632/aging.203950
pp 2018—2019
As predicted by hyperfunction theory, rapamycin treatment during development extends lifespan
Mikhail V. Blagosklonny1
doi : 10.18632/aging.203937
Volume 14, Issue 5 pp 2020—2024
Depletion of transmembrane mucin 4 (Muc4) alters intestinal homeostasis in a genetically engineered mouse model of colorectal cancer
Ramesh Pothuraju1 , Priya Pai1, * , Sanjib Chaudhary1, * , Jawed A. Siddiqui1 , Jesse L. Cox2 , Sukhwinder Kaur1 , Satyanarayana Rachagani1 , Hemant K. Roy3 , Michael Bouvet4,5 , Surinder K. Batra1,6,7
doi : 10.18632/aging.203935
Volume 14, Issue 5 pp 2025—2046
Mucins are components of the mucus layer overlying the intestinal epithelial cells, which maintains physiological homeostasis. Altered mucin expression is associated with disease progression. Expression of MUC4 decreases in colorectal cancer (CRC); however, its functional role and implications in the intestinal pathology in CRC are not studied well. Therefore, we generated a genetically engineered Muc4 knockout (Muc4-/-) CRC mouse model by crossing with Muc4-/- and Apcflox/flox mice in the presence of colon-specific inducible Cre. We observed that deficiency of Muc4 results in an increased number of macroscopic tumors in the colon and rectal region and leads to poor survival. Further, the absence of Muc4 was associated with goblet cell dysfunction where the expression of intestinal homeostasis molecules (Muc2 and Fam3D) was downregulated. Next, we also observed that loss of Muc4 showed reduced thickness of mucus layer, leading to infiltration of bacteria, reduction in anti-microbial peptides, and upregulation of pro-inflammatory cytokines. Further, Apc gene mutation results in activation of the Wnt/β-catenin signaling pathway that corroborated with an increased nuclear accumulation of β-catenin and activation of its target genes: cyclin D1 and c-Myc in Muc4-/- mice was observed. We conclude that the presence of Muc4 is essential for intestinal homeostasis, reduces tumor burden, and improves overall survival.
Cell immortalization facilitates prelamin A clearance by increasing both cell proliferation and autophagic flux
Carlos González-Blanco1 , Patricia Marqués1 , Jesús Burillo1,3 , Beatriz Jiménez1 , Gema GarcÃa1 , Manuel Benito1,2,3, * , Carlos Guillén1,2,3, *
doi : 10.18632/aging.203943
Volume 14, Issue 5 pp 2047—2061
Hutchinson-Gilford Progeria Syndrome is an ultrarare disease which is characterized by an accelerated senescence phenotype with deleterious consequences to people suffering this pathology. The production of an abnormal protein derived from lamin A, called progerin, presents a farnesylated domain, which is not eliminated by the causal mutation of the disease, and accumulates in the interior of the nucleus, provoking a disruption of nuclear membrane, chromatin organization and an altered gene expression. The mutation in these patients occurs in a single nucleotide change, which creates a de novo splicing site, producing a shorter version of the protein. Apart from this mutation, an alteration in the metalloproteinase Zmpste24, involved in the maturation of lamin A, causing a similar alteration than in progeria. However, in this case, patients accumulate a protein, called prelamin A, which generates similar alterations in the nucleus than progerin. The reduction of prelamin A protein levels facilitates the recovery of the phenotype in different mice models of the disease, reducing the aging process. Different strategies have been studied for eliminating this toxic protein. Here, we report that immortalization of primary cells derived from the Zmpste24 KO mice, facilitates prelamin A degradation by different mechanisms, being essential, the enhancing proliferative capacity that the immortalized cells present. Then, these data suggest that using different treatments for increasing proliferative capacity of these cells, potentially could have a beneficial effect, facilitating prelamin A toxicity.
Association of active immunotherapy with outcomes in cancer patients with COVID-19: a systematic review and meta-analysis
Chang Cao1, * , Xinyan Gan1, * , Xiaolin Hu2, * , Yonglin Su3 , Yu Zhang4 , Xingchen Peng3
doi : 10.18632/aging.203945
Volume 14, Issue 5 pp 2062—2080
Background: During the COVID-19 pandemic, there are growing concerns about the safety of administering immunotherapy in cancer patients with COVID-19. However, current clinical guidelines provided no clear recommendation.
Modulation of RNA splicing associated with Wnt signaling pathway using FD-895 and pladienolide B
Deepak Kumar1,2, * , Manoj K. Kashyap1,3, * , Zhe Yu1 , Ide Spaanderman1 , Reymundo Villa4 , Thomas J. Kipps1,5 , James J. La Clair4 , Michael D. Burkart4 , Januario E. Castro1,5,6
doi : 10.18632/aging.203924
Volume 14, Issue 5 pp 2081—2100
Alterations in RNA splicing are associated with different malignancies, including leukemia, lymphoma, and solid tumors. The RNA splicing modulators such as FD-895 and pladienolide B have been investigated in different malignancies to target/modulate spliceosome for therapeutic purpose. Different cell lines were screened using an RNA splicing modulator to test in vitro cytotoxicity and the ability to modulate RNA splicing capability via induction of intron retention (using RT-PCR and qPCR). The Cignal Finder Reporter Array evaluated [pathways affected by the splice modulators in HeLa cells. Further, the candidates associated with the pathways were validated at protein level using western blot assay, and gene-gene interaction studies were carried out using GeneMANIA. We show that FD-895 and pladienolide B induces higher apoptosis levels than conventional chemotherapy in different solid tumors. In addition, both agents modulate Wnt signaling pathways and mRNA splicing. Specifically, FD-895 and pladienolide B significantly downregulates Wnt signaling pathway-associated transcripts (GSK3β and LRP5) and both transcript and proteins including LEF1, CCND1, LRP6, and pLRP6 at the transcript, total protein, and protein phosphorylation’s levels. These results indicate FD-895 and pladienolide B inhibit Wnt signaling by decreasing LRP6 phosphorylation and modulating mRNA splicing through induction of intron retention in solid tumors.
Pathway-based metabolomics study of sarcopenia-related traits in two US cohorts
Qi Zhao1, * , Hui Shen2, * , Jiawang Liu3,4 , Chi-Yang Chiu1 , Kuan-Jui Su2 , Qing Tian2 , David Kakhniashvili5 , Chuan Qiu2 , Lan-Juan Zhao2 , Zhe Luo2 , Hong-Wen Deng2
doi : 10.18632/aging.203926
Volume 14, Issue 5 pp 2101—2112
We aimed to validate two metabolites, aspartic acid and glutamic acid, which were associated with sarcopenia-related traits, muscle mass and strength, in our previous untargeted metabolomics study and to identify novel metabolites from five metabolic pathways involving these two metabolites. We included a discovery cohort of 136 white women aged 20-40 years (used for the previous untargeted metabolomics analysis) and a validation cohort of 174 subjects aged ≥ 60 years, including men and women of white and black. A targeted LC-MS assay successfully detected 12 important metabolites from these pathways. Aspartic acid was associated with muscle mass and strength in the discovery cohort, but not in the validation cohort. However, glutamic acid was associated with these sarcopenia traits in both cohorts. Additionally, N-acetyl-L-aspartic acid and carnosine were the newly identified metabolites that were associated with muscle strength in the discovery and validation cohorts, respectively. We did not observe any significant sex and race differences in the associations of these metabolites with sarcopenia traits in the validation cohort. Our findings indicated that glutamic acid might be consistently associated with sarcopenia-related traits across age, sex, and race. They also suggested that age-specific metabolites and metabolic pathways might be involved in muscle regulation.
Human endothelial cells promote arsenic-transformed lung epithelial cells to induce tumor growth and angiogenesis through interleukin-8 induction
Lei Zhao1 , Yi-Fang Wang2 , Jie Liu2 , Bing-Hua Jiang2 , Ling-Zhi Liu1
doi : 10.18632/aging.203930
Volume 14, Issue 5 pp 2113—2130
Arsenic exposure is associated with lung cancer. Angiogenesis is essential for tumor development. However, the role and mechanism of human vascular endothelial cells in tumor growth and angiogenesis induced by arsenic-transformed bronchial epithelial (As-T) cells remain to be elucidated. In this study, we found that endothelial cells significantly increased As-T cell-induced tumor growth compared to those induced by As-T cells alone. To understand the molecular mechanism, we found that endothelial cells co-cultured with As-T cells or cultured in conditioned medium (CM) prepared from As-T cells showed much higher cell migration, proliferation, and tube formation compared to those co-cultured with BEAS-2B (B2B) cells or cultured in CM from B2B. We identified that higher levels of intracellular interleukin 8 (IL-8) were secreted by As-T cells, which activated IL-8/IL-8R signaling to promote endothelial cells migration and tube formation. IL-8 silencing and knockout (KO) in As-T cells, or IL-8 neutralizing antibody dramatically suppressed endothelial cell proliferation, migration, tube formation in vitro, and tumor growth and angiogenesis in vivo, suggesting a key role of IL-8 in As-T cells to induce angiogenesis via a paracrine effect. Finally, blocking of IL-8 receptors C-X-C chemokine receptor type 1 (CXCR1) and CXCR2 with neutralizing antibodies and chemical inhibitors inhibited tube formation, indicating that IL-8Rs on endothelial cells are necessary for As-T cell-induced angiogenesis. Overall, this study reveals an important molecular mechanism of arsenic-induced carcinogenesis, and suggests a new option to prevent and treat arsenic-induced angiogenesis.
Enhanced co-culture and enrichment of human natural killer cells for the selective clearance of senescent cells
Kristie Kim1 , Tesfahun Dessale Admasu1 , Alexandra Stolzing1,2 , Amit Sharma1
doi : 10.18632/aging.203931
Volume 14, Issue 5 pp 2131—2147
In the context of aging and age-associated diseases, Natural Killer (NK) cells have been revealed as a key cell type responsible for the immune clearance of senescent cells. Subsequently, NK cell-based therapies have emerged as promising alternatives to drug-based therapeutic interventions for the prevention and treatment of age-related disease and debility. Given the promise of NK cell-mediated immunotherapies as a safe and effective treatment strategy, we outline an improved method by which primary NK cells can be efficiently enriched from human peripheral blood across multiple donors (ages 20-42 years old), with a practical protocol that reliably enhances both CD56dim and CD56bright NK cells by 15-fold and 3-fold, respectively. Importantly, we show that our co-culture protocol can be used as an easily adaptable tool to assess highly efficient and selective killing of senescent cells by primary NK cells enriched via our method using longer co-culture durations and a low target to effector ratio, which may be more physiological than has been achieved in previous literature.
Parkinson’s disease and cancer: a systematic review and meta-analysis on the influence of lifestyle habits, genetic variants, and gender
Joon Yan Selene Lee1 , Jing Han Ng2 , Seyed Ehsan Saffari1,2 , Eng-King Tan1,2
doi : 10.18632/aging.203932
Volume 14, Issue 5 pp 2148—2173
Purpose: The relationship between Parkinson’s disease (PD) and cancer has been debated. Gender and genetic influences on cancer development in PD is unclear.
Increased DNA methylation, cellular senescence and premature epigenetic aging in guinea pigs and humans with tuberculosis
Carly A. Bobak1, * , Abhimanyu2,3,4, * , Harini Natarajan5 , Tanmay Gandhi6,7 , Sandra L. Grimm6,7 , Tomoki Nishiguchi2,3,4 , Kent Koster8 , Santiago Carrero Longlax2,3,4 , Qiniso Dlamini9 , Jacquiline Kahari9 , Godwin Mtetwa9 , Jeffrey D. Cirillo8 , James O’Malley1,10, # , Jane E. Hill11, # , Cristian Coarfa6,7, # , Andrew R. DiNardo2,3,4, #
doi : 10.18632/aging.203936
Volume 14, Issue 5 pp 2174—2193
Background: Tuberculosis (TB) is the archetypical chronic infection, with patients having months of symptoms before diagnosis. In the two years after successful therapy, survivors of TB have a three-fold increased risk of death.
Tonsil mesenchymal stem cells-derived extracellular vesicles prevent submandibular gland dysfunction in ovariectomized rats
Ji Min Kim1 , Jeong Hun Kim2 , Keunyoung Kim3 , Sung-Chan Shin4 , Yong-Il Cheon4 , Hyung Sik Kim5,6 , Jin-Choon Lee7 , Eui-Suk Sung7 , Minhyung Lee7 , Gi-Cheol Park8 , Byung-Joo Lee2,4
doi : 10.18632/aging.203947
Volume 14, Issue 5 pp 2194—2209
Dry mouth that occurs after menopause significantly reduces the quality of life of the elderly. The extracellular vesicles derived from mesenchymal stem cells are being studied for application in various pathological conditions in the field of tissue regenerative medicine. This study is to investigate the therapeutic effect on salivary gland dysfunction occurring after ovariectomy using tonsil mesenchymal stem cells (T-MSCs)-derived extracellular vesicles. The rats were divided into the following groups: sham-operated rats (SHAM), rats that underwent ovariectomy (OVX), and rats that underwent OVX surgery and were simultaneously injected with T-MSC-derived extracellular vesicles (OVX+EV). The rats were sacrificed 6 weeks after ovariectomy. Estradiol levels decreased in the OVX group compared with those in the SHAM group. Extracellular vesicles had no effect on estradiol levels or estrogen receptor β expression. The evaluation of pro-inflammatory cytokines, TNF-α and IL-6, increased in the OVX group and decreased in the OVX+EV group. The expressions of collagen I and TGFβI increased in the OVX group but decreased in the OVX+EV group. Moreover, to examine submandibular gland function, AQP5 and α-amylase expressions were downregulated in the OVX group, but improved upon exosome injection. In conclusion, T-MSC-derived extracellular vesicles are useful for the prevented submandibular gland dysfunction that occurs after menopause.
Circular RNA circ_0001006 aggravates cardiac hypertrophy via miR-214-3p/PAK6 axis
Xuefeng Lin1,2,3,4,5,6 , Liqin Zhang6 , Wei Zhang7 , Xinjun Lei1 , Qun Lu1 , Aiqun Ma1,2,3,4
doi : 10.18632/aging.203461
Volume 14, Issue 5 pp 2210—2220
Aim: Circular RNAs (circRNAs) control gene expression in a series of physiological and pathological processes, but their role in heart disease is unknown. This research illustrates the role and potential mechanism of circRNA in cardiac hypertrophy.
Impact of the food grade heat-killed probiotic and postbiotic oral lozenges in oral hygiene
Chiao-Wen Lin1,2 , Yi-Tzu Chen1,2,3 , Hsieh-Hsun Ho4 , Yi-Wei Kuo4 , Wen-Yang Lin4 , Jui-Fen Chen4 , Jia-Hung Lin4 , Cheng-Ruei Liu4 , Chi-Huei Lin4 , Yao-Tsung Yeh5 , Ching-Wei Chen4 , Yu-Fen Huang4 , Chen-Hung Hsu4 , Pei-Shan Hsieh4 , Shun-Fa Yang6,7
doi : 10.18632/aging.203923
Volume 14, Issue 5 pp 2221—2238
The oral cavity plays a crucial role in food digestion and immune protection. Thus, maintaining oral health is necessary. Postbiotic and heat-killed probiotic cells have shown increased antibacterial potential with stable viability compared with live strains. However, clinical evidence regarding their effect on oral health is insufficient. Therefore, in this study, we tested postbiotic lozenges of Lactobacillus salivarius subsp. salicinius AP-32, L. paracasei ET-66, and L. plantarum LPL28 and heat-killed probiotic lozenges of L. salivarius subsp. salicinius AP-32 and L. paracasei ET-66 for their effect on oral health. In total, 75 healthy individuals were blindly and randomly divided into placebo, postbiotic lozenge, and heat-killed probiotic lozenge groups and were administered the respective lozenge type for 4 weeks. Postbiotic and heat-killed probiotic lozenge groups demonstrated antibacterial activities with a considerable increase in L. salivarius in their oral cavity. Furthermore, their salivary immunoglobulin A, Lactobacillus, and Bifidobacterium increased. Subjective questionnaires completed by the participants indicated that participants in both the experimental groups developed better oral health and intestinal conditions than those in the placebo group. Overall, our study revealed that a food additive in the form of an oral postbiotic or heat-killed probiotic lozenge may effectively enhance oral immunity, inhibit the growth of oral pathogens, and increase the numbers of beneficial oral microbiota.
The association between osteoporosis medications and lowered all-cause mortality after hip or vertebral fracture in older and oldest-old adults: a nationwide population-based study
Chia-Chun Li1,2, * , Jason C. Hsu3,4,5,9, * , Fu-Wen Liang6 , Yin-Fan Chang7 , Ching-Ju Chiu1,8 , Chih-Hsing Wu2,7,8
doi : 10.18632/aging.203927
Volume 14, Issue 5 pp 2239—2251
Background: Osteoporotic fracture is a common public-health problem in ageing societies. Although post-fracture usage of osteoporosis medications may reduce mortality, recent results have been inconsistent. We aimed to examine associations between osteoporosis medication and mortality in older adults, particularly oldest-old adults (>=85 years old).
Downregulation of ATP binding cassette subfamily a member 10 acts as a prognostic factor associated with immune infiltration in breast cancer
Pei-Yi Chu1,2,3,4,5 , Yen-Dun Tony Tzeng6,7 , Kuan-Hao Tsui8 , Ching-Yu Chu8 , Chia-Jung Li8,9
doi : 10.18632/aging.203933
Volume 14, Issue 5 pp 2252—2267
The human ATP binding cassette (ABC) family of transporter proteins plays an important role in the maintenance of homeostasis in vivo. The aim of this study is to evaluate the potential diagnostic, prognostic, and therapeutic value of the ABCA10 gene in BRCA. We found that ABCA10 expression was downregulated in different subgroups of breast cancer and strongly correlated with pathological stage in BRCA patients. Low expression of ABCA10 was associated with BRCA patients showing shorter overall survival (OS). ABCA10 expression may be regulated by promoter methylation, copy number variation (CNV) and kinase, and is associated with immune infiltration. Our study also demonstrated the potential role of ABCA10 modifications in tumor microenvironment (TME) cellular infiltration. Nevertheless, the regulatory mechanism remains unknown and immunotherapy is marginal in BRCA. We demonstrate the expression of different ABCA10 modulators in breast cancer associated with genetic variants, deletions, tumor mutation burden (TMB) and TME. Mutations in ABCA10 are positively associated with different immune cells in six different immune databases and play an important role in immune cell infiltration in breast cancer. Overall, this study provides evidence that ABCA10 could become the potential targets for precision treatment and new biomarkers in the prognosis of breast cancer.
A comprehensive analysis of FOX family in HCC and experimental evidence to support the oncogenic role of FOXH1
Xiwu Ouyang1 , Lemeng Feng1 , Lei Yao1 , Jingyu Zhang1 , Yao Xiao2 , Guodong Liu3 , Gewen Zhang1 , Zhiming Wang1
doi : 10.18632/aging.203934
Volume 14, Issue 5 pp 2268—2286
Hepatocellular carcinoma (HCC) remains the second leading cause of cancer related deaths worldwide. Understanding about the molecular biology of HCC and development of targeted therapies are still the main focuses of this type of disease. Here, by connecting the expression levels of FOX proteins with their associated clinical characteristics using TCGA LIHC dataset, we found that 27/40 FOX proteins were highly expressed in HCC tumors compared to normal liver tissues and their expression levels were tightly associated with HCC tumor stage, tumor grade and overall survival. Our experimental results also confirmed that FOXH1 indeed played an oncogenic role in HCC development by promoting cell growth and cell migration/invasion. Mechanistic dissection demonstrated that FOXH1-induced cell growth and cell migration/invasion relied on mTOR signaling because inhibition of mTOR signaling by rapamycin could attenuate FOXH1-mediated phenotypic alterations of HCC cells. The results from orthotopic mouse model also validated that FOXH1 promoted HA22T tumor growth via triggering mTOR activation. Overall, this study not only comprehensively examines the clinical values of FOX proteins in HCC but also provides experimental evidence to support the role of FOXH1 in HCC development, building rationale to develop more effective therapies to treat HCC patients.
MafK accelerates Salmonella mucosal infection through caspase-3 activation
Shiyao Xu1, * , Guiqiu Hu1, * , Di Wu1 , Xingchi Kan1 , Hisashi Oishi2 , Satoru Takahashi3 , Shoupeng Fu1 , Juxiong Liu1 , Chuan Zhang4
doi : 10.18632/aging.203938
Volume 14, Issue 5 pp 2287—2303
Gastrointestinal homeostasis is critical for maintaining host health, and is affected by many factors. A recent report showed that Musculoaponeurotic fibrosarcoma K (MafK) expression is increased in patients that have ulcerative colitis (UC). Even so, MafK’s significance in sustaining intestinal homeostasis has not been investigated. In this research, MafK overexpressing transgenic (MafK Tg) mice were found to be more susceptible to infection with Salmonella on the mucosa than the wild-type (WT) mice. Following Salmonella oral infection, MafK Tg mice suffered higher mortality and a lot more weight loss, damage to the intestines, and inflammation in the intestines than WT mice. MafK Tg mice were also unable to control Salmonella colonization and dissemination. In vivo data showed that increased MafK expression promoted epithelial cell apoptosis which was further confirmed by in vitro data. The rapid cleavage of caspase-3 in epithelial cells contributed to Salmonella dissemination and inflammation initiation. This study reveals that MafK participates in Salmonella pathogenesis acceleration by increasing caspase-3 activation.
Downregulation of ZC3H13 by miR-362-3p/miR-425-5p is associated with a poor prognosis and adverse outcomes in hepatocellular carcinoma
Shuang Wu1,2 , Shihai Liu3 , Yongxian Cao1 , Geng Chao1 , Peng Wang4 , Huazheng Pan1
doi : 10.18632/aging.203939
Volume 14, Issue 5 pp 2304—2319
Hepatocellular carcinoma (HCC) is notorious for its poor prognosis. Previous studies identified several N6-methyladenosine (m6A)-related genes that play key roles in the initiation and progression of HCC patients. In particular, the N6-methyladenosine RNA methylation regulator ZC3H13 could be a candidate as a novel biomarker and therapeutic target for hepatocellular carcinoma. In HCC, low expression of ZC3H13 was reported, but the molecular reason is unclear. In this study, we performed pan cancer analysis for ZC3H13 expression and prognosis using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) data and found that ZC3H13 might be a potential tumor suppressor gene in HCC. Subsequently, miRNAs contributing to ZC3H13 downregulation were identified by a series of in silico analyses, including expression analysis, correlation analysis, and survival analysis. Finally, the miR-362-3p/miR-425-5p-ZC3H13 axis was identified as the most likely upstream miRNA-related pathway of ZC3H13 in HCC. Additionally, miR-362-3p/miR-425-5p mimic and inhibitor results were detected by quantitative real-time PCR (qPCR) analysis and western blotting. We identified an upstream regulatory mechanism of ZC3H13 in HCC, namely, the miR-362-3p/miR-425-5p-ZC3H13 axis. Moreover, the ZC3H13 level was significantly positively associated with tumor immune cell infiltration, biomarkers of immune cells, and immune checkpoint expression. Collectively, our findings elucidated that ncRNA-mediated downregulation of ZC3H13 was correlated with a poor prognosis and tumor immune infiltration in HCC. In conclusion, this study demonstrates that ZC3H13 is a direct target of miR-362-3p/miR-425-5p in liver hepatocellular carcinoma (LIHC) that regulates immune modulation in the microenvironment of LIHC.
Polo-like kinases as potential targets and PLK2 as a novel biomarker for the prognosis of human glioblastoma
Yiming Ding1, * , Hanjie Liu2, * , Chuanbao Zhang1 , Zhaoshi Bao1 , Shuqing Yu1
doi : 10.18632/aging.203940
Volume 14, Issue 5 pp 2320—2334
The most prevalent malignant central nervous system (CNS) cancer is glioblastoma multiforme (GBM). PLKs (polo-like kinases) are a kind of serine-threonine kinase that modulate DNA replication, mitosis, and stress responses. PLKs in GBM need to be better studied and examined in terms of their expression, function, along with prognostic significance. Using an existing publicly available data set, we evaluated the expression level and prognostic relevance of PLKs in GBM patients at the molecular level. The biological processes along with cascades of the screened gene were predicted using the functional enrichment of Gene Set Enrichment Analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathways. The data illustrated that PLK1/3/4 contents were greater in GBM tissues than in non-tumorous tissues, but PLK2/5 expression levels were lower. PLK2 expression was also linked to patient outcome in GBM. Our findings imply that PLKs might be useful molecular indicators as well as prospective treatment targets for GBM. A PLK2 inhibitor has been studied for the first time in a glioma cell in this work. In glioma cells, ON1231320 has anticancer effects. Finally, a summary of PLK inhibitors is presented, along with projections for future progress.
Decrease in ovarian reserve through the inhibition of SIRT1-mediated oxidative phosphorylation
Lu Guo1,2 , Xiaocheng Liu1,2, * , Hua Chen1,2 , Weigui Wang1,2 , Chao Gu1,2, * , Bin Li1,2
doi : 10.18632/aging.203942
Volume 14, Issue 5 pp 2335—2347
Objective: To establish an oxidative stress-induced model of premature ovarian insufficiency (POI) and to explore the effect of SIRT1 and mitochondrial oxidative phosphorylation on the ovarian reserve.
Functional implications of aging-related lncRNAs for predicting prognosis and immune status in glioma patients
Guangying Zhang1 , Yanyan Li2 , Na Li1 , Liang-Fang Shen1 , Zhanzhan Li1,3
doi : 10.18632/aging.203944
Volume 14, Issue 5 pp 2348—2366
This study is aimed to establish a new glioma prognosis model by integrating the aging-related lncRNA expression profiles and clinical parameters of glioma patients enrolled in the Chinese Glioma Genome Atlas and The Cancer Genome Atlas. The aging-related lncRNAs were explored using Pearson correlation analysis (|R|> 0.6, P < 0.001), and the prognostic signature in glioma patients was screened using univariate cox regression and least absolute shrinkage/selection operator regression. Based on the fifteen lncRNAs screened out, we divided the glioma patients into three subtypes, and developed a prognostic model. Kaplan-Meier survival curve analysis showed that low-risk patients survived longer time than high-risk patients. Principal component analysis indicated that the signature of aging-related lncRNAs was clearly distinct between the high- and low-risk groups. We also found the fifteen lncRNAs were closely correlated with 119 genes by establishing a co-expression network. Kyoto Encyclopedia of Genes and Genomes analysis displayed that the high- and low-risk groups were enriched in different functions and pathways. Different missense mutations were observed in the two groups, and the most frequent variant types were single nucleotide polymorphism. This study demonstrates that the novel aging-related lncRNAs signature has an important prognosis prediction ability and may contribute to individualized treatment for glioma.
Centrosomal protein 290 is a novel prognostic indicator that modulates liver cancer cell ferroptosis via the Nrf2 pathway
Yiru Shan1, * , Guang Yang2, * , Qiuhong Lu3, * , Xiangyu Hu4, * , Dongwei Qi4, * , Yehan Zhou5 , Yin Xiao1 , Li Cao6, & , Fuhua Tian1, & , Qi Pan4
doi : 10.18632/aging.203946
Volume 14, Issue 5 pp 2367—2382
Ferroptosis is an iron-dependent form of cell death. In spite of its significance in pathogenesis and disease progression, ferroptotic signal transduction in HBV-HCC has not been fully explained. Here, four HCC open-source datasets were downloaded from the GEO repository. Cox regression and LASSO models were established to prioritize novel prognostic candidate biomarkers, and the results were verified in vitro and in vivo. We identified 633 common DEGs in both of the bulk RNA-Seq expression profiles. Next, based upon the TCGA-LIHC cohort, a prognostic signature consisting of nine genes was extracted from 633 shared DEGs, and the specificity and sensitivity of the signature were evaluated in both training and validation datasets. This signature showed that the high-risk group had a worse prognosis than the low-risk group. CEP290 was discovered among the prognostic signature genes, and its expression notably correlated with survival, AFP level, TNM stage and vascular invasion. We confirmed expression of CEP290 in eight pairs of HCC tissues and diverse liver cancer cell lines. CEP290 knockdown reduced proliferation, migration and invasion in Hep3B liver cancer cells while Fe2+ and malondialdehyde levels were elevated. Mechanically, co-immunoprecipitation showed an interaction between CEP290 and Nrf2 proteins, and biological phenotypes of Hep3B cells under CEP290 interference were rescued by Nrf2 activator. Furthermore, CEP290 silencing considerably blocked protein expression of Nrf2 pathway members. Finally, suppression of CEP290 effectively inhibited tumor growth in vivo. The above results shed light on the important role of CEP290 in ferroptosis and present an important implication for HCC progression.
Establishing a cancer driver gene signature-based risk model for predicting the prognoses of gastric cancer patients
Jun Chen1 , Chao Zhou2 , Ying Liu3
doi : 10.18632/aging.203948
Volume 14, Issue 5 pp 2383—2399
Despite the high prevalence of gastric cancer (GC), molecular biomarkers that can reliably detect GC are yet to be discovered. The present study aimed to establish a robust gene signature based on cancer driver genes (CDGs) that can predict GC prognosis. Transcriptional profiles and clinical data from GC patients were analyzed using univariate Cox regression analysis and the least absolute shrinkage and selection (LASSO)-penalized Cox regression analysis to select optimal prognosis-related genes for modeling. Time-dependent receiver operating characteristic (ROC) and Kaplan-Meier analyses were done to assess the predictive power of this gene signature. A nomogram model for prediction of survival of GC patients was established using the CDG signature and clinical information, and a seven-CDG signature was identified. Risk scores were calculated using this signature, and patients were subsequently divided into high- and low-risk groups; high-risk patients in the training and validation datasets had poorer prognoses than low-risk patients. Cox regression analysis revealed that the CDG signature is an independent prognostic factor for GC. The signature and other clinical features were used to construct a nomogram for predicting overall GC patient survival. Calibration and decision curve analysis showed that the nomogram accurately predicted survival, highlighting its clinical utility. Thus, we established a novel CDG signature and nomogram for predicting GC prognosis, which may facilitate personalized treatment of GC.
Manual therapy regulates oxidative stress in aging rat lumbar intervertebral discs through the SIRT1/FOXO1 pathway
Chongjie Yao1,2, * , Guangxin Guo1,4, * , Ruixin Huang2 , Cheng Tang2 , Qingguang Zhu2,3 , Yanbin Cheng2,3 , Lingjun Kong2,3 , Jun Ren2 , Min Fang1,2,3
doi : 10.18632/aging.203949
Volume 14, Issue 5 pp 2400—2417
With the increasing burden of a globally aging population, low back pain has become one of the most common musculoskeletal disorders, caused mainly by intervertebral disc (IVD) degeneration. There are currently several clinical methods to alleviate back pain, but there is scarce attention paid as to whether they can improve age-related IVD degeneration. It is therefore difficult to conduct an in-depth evaluation of these methods. A large number of clinical studies have shown that manual therapy (MT), a widely used comprehensive alternative method, has effects on pain, the mechanisms of which require further study. In this study, MT was performed on aging rats for 6 months, and their behaviors were compared with those of a non-intervention group of aging and young rats. After the intervention, all rats were examined by X-ray to observe lumbar spine degeneration, and the IVD tissues were dissected for detection, including pathological staining, immunofluorescence, Western bolt, etc. This study demonstrated the possibility that MT intervention delay the lumbar IVD degeneration in aging rats, specifically improving the motor function and regulating senescence-associated β-galactosidase, p53, p21, p16, and telomerase activity to retard the senescence of cells in IVDs. Moreover, MT intervention can modify oxidative stress, increase the expression of SIRT1 and FOXO1 in IVDs and decrease ac-FOXO1 expression, suggesting that MT can reduce oxidative stress through the SIRT1/FOXO1 pathway, thereby playing a role in delaying the aging of IVDs. This study shows that drug-free, non-invasive mechanical interventions could be of major significance in improving the physical function of the elderly.
miRNA-29a inhibits atherosclerotic plaque formation by mediating macrophage autophagy via PI3K/AKT/mTOR pathway
Weihua Shao1 , Suxing Wang2 , Xiaoxi Wang3 , Lixia Yao2 , Xiaoye Yuan2 , Dai Huang4 , Bonan Lv5 , Yuquan Ye6 , Hongyuan Xue4
doi : 10.18632/aging.203951
Volume 14, Issue 5 pp 2418—2431
Background: miR-29a plays a vital role in AS, but the relationship between the miR-29a-targeted PI3K signaling pathway and AS remains unclear. Therefore, this study was carried out.
Correction for: circUBAP2 exacerbates malignant capabilities of NSCLC by targeting KLF4 through miR-3182 modulation
Guanying Zheng1, * , Jianyuan Huang2, * , Wenshu Chen2 , Peilin You2 , Yun Ding2 , Pengjie Tu2
doi : 10.18632/aging.203928
Volume 14, Issue 5 pp 2432—2433
Correction for: Calycosin stimulates the proliferation of endothelial cells, but not breast cancer cells, via a feedback loop involving RP11-65M17.3, BRIP1 and ERα
Yong Wang1, * , Wei Xie1, * , Mengyue Hou1, * , Jing Tian2 , Xing Zhang1 , Qianyao Ren1 , Yue Huang3 , Jian Chen1
doi : 10.18632/aging.203953
Volume 14, Issue 5 pp 2434—2435
