Aging

Vera Gorbunova1 , Marcus Buschbeck2,3 , Xiaolu A. Cambronne4 , Karthikeyani Chellappa5 , Daniela Corda6 , Juan Du7 , Marc Freichel8 , Jonathan Gigas9 , Alexander E. Green10,11 , Feng Gu12 , Iva Guberovic2 , Aravinthkumar Jayabalan13 , Imrankhan Khansahib12 , Sarmistha Mukherjee5 , Andrei Seluanov1 , Matthew A. Simon9 , Lars J. Sverkeli14 , Nora Kory15 , Daniel C. Levine16 , Ivan Matic17 , Andrey Nikiforov18 , Johannes G.M. Rack19 , Shin-Ichiro Imai20,21 , David A. Sinclair22 , Debra Toiber23 , Yongjuan Zhao24 , Raul Mostoslavsky25,26 , Lee Kraus27,28 , Andreas H. Guse12

doi : 10.18632/aging.203766

Volume 13, Issue 23, pp: 24924—24930

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Multicenter study evaluating one multiplex RT-PCR assay to detect SARS-CoV-2, influenza A/B, and respiratory syncytia virus using the LabTurbo AIO open platform: epidemiological features, automated sample-to-result, and high-throughput testing

Hsing-Yi Chung1, * , Ming-Jr Jian1, * , Chih-Kai Chang1 , Jung-Chung Lin2 , Kuo-Ming Yeh2 , Ya-Sung Yang2 , Chien-Wen Chen3 , Shan-Shan Hsieh1 , Sheng-Hui Tang1 , Cherng-Lih Perng1 , Feng-Yee Chang2 , Kuo-Sheng Hung4 , En-Sung Chen5 , Mei-Hsiu Yang5 , Hung-Sheng Shang1

doi : 10.18632/aging.203761

Volume 13, Issue 23, pp: 24931—24942

Since the Coronavirus 19 (COVID-19) pandemic, several SARS-CoV-2 variants of concern (SARS-CoV-2 VOC) have been reported. The B.1.1.7 variant has been associated with increased mortality and transmission risk. Furthermore, cluster and possible co-infection cases could occur in the next influenza season or COVID-19 pandemic wave, warranting efficient diagnosis and treatment decision making. Here, we aimed to detect SARS-CoV-2 and other common respiratory viruses using multiplex RT-PCR developed on the LabTurbo AIO 48 open system. We performed a multicenter study to evaluate the performance and analytical sensitivity of the LabTurbo AIO 48 system for SARS-CoV-2, influenza A/B, and respiratory syncytial virus (RSV) using 652 nasopharyngeal swab clinical samples from patients. The LabTurbo AIO 48 system demonstrated a sensitivity of 9.4 copies/per PCR for N2 of SARS-CoV-2; 24 copies/per PCR for M of influenza A and B; and 24 copies/per PCR for N of RSV. The assay presented consistent performance in the multicenter study. The multiplex RT-PCR applied on the LabTurbo AIO 48 open platform provided highly sensitive, robust, and accurate results and enabled high-throughput detection of B.1.1.7, influenza A/B, and RSV with short turnaround times. Therefore, this automated molecular diagnostic assay could enable streamlined testing if COVID-19 becomes a seasonal disease.

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Impact of chemotherapy and immunotherapy on the composition and function of immune cells in COVID-19 convalescent with gynecological tumors

Tianyu Qin1,2 , Ensong Guo1,2 , Funian Lu1,2 , Yu Fu1,2 , Si Liu1,2 , Rourou Xiao1,2 , Xue Wu1,2 , Chen Liu1,2 , Chao He1,2 , Zizhuo Wang1,2 , Xu Qin1,2 , Dianxing Hu1,2 , Lixin You1,2 , Fuxia Li3 , Xi Li1,2,4 , Xiaoyuan Huang1,2 , Ding Ma1,2 , Xiaoyan Xu1,2 , Bin Yang1,2 , Junpeng Fan1,2

doi : 10.18632/aging.203739

Volume 13, Issue 23, pp: 24943—24962

Ongoing pandemic and potential resurgence of Coronavirus disease 2019 (COVID-19) has prompted urgent efforts to investigate the immunological memory of convalescent patients, especially in patients with active cancers. Here we performed single-cell RNA sequencing in peripheral blood samples of 3 healthy donors (HDs), 4 COVID-19 patients (Covs) and 4 COVID-19 patients with active gynecological tumor (TCs) pre- and post- anti-tumor treatment. All Covs patients had recovered from their acute infection. Interestingly, the molecular features of PBMCs in TCs are similar to that in Covs, suggesting that convalescent COVID-19 with gynecologic tumors do not have major immunological changes and may be protected against reinfection similar to COVID-19 patients without tumors. Moreover, the chemotherapy given to these patients mainly caused neutropenia, while having little effect on the proportion and functional phenotype of T and B cells, and T cell clonal expansion. Notably, anti-PD-L1 treatment massively increased cytotoxic scores of NK cells, and T cells, and facilitated clonal expansion of T cells in these patients. It is likely that T cells could protect patients from SARS-CoV-2 virus reinfection and anti-PD-L1 treatment can enhance the anti-viral activity of the T cells.

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Metabolomic profiling of plasma from middle-aged and advanced-age male mice reveals the metabolic abnormalities of carnitine biosynthesis in metallothionein gene knockout mice

Yoshito Kadota1 , Asuka Yano1 , Takashige Kawakami1 , Masao Sato1 , Shinya Suzuki1

doi : 10.18632/aging.203731

Volume 13, Issue 23, pp: 24963—24988

Metallothionein (MT) is a family of low molecular weight, cysteine-rich proteins that regulate zinc homeostasis and have potential protective effects against oxidative stress and toxic metals. MT1 and MT2 gene knockout (MTKO) mice show shorter lifespans than wild-type (WT) mice. In this study, we aimed to investigate how MT gene deficiency accelerates aging. We performed comparative metabolomic analyses of plasma between MTKO and WT male mice at middle age (50-week-old) and advanced age (100-week-old) using liquid chromatography with time-of-flight mass spectrometry (LC-TOF-MS). The concentration of N6,N6,N6-trimethyl-L-lysine (TML), which is a metabolic intermediate in carnitine biosynthesis, was consistently higher in the plasma of MTKO mice compared to that of WT mice at middle and advanced age. Quantitative reverse transcription PCR (RT-PCR) analysis revealed remarkably lower mRNA levels of Tmlhe, which encodes TML dioxygenase, in the liver and kidney of male MTKO mice compared to that of WT mice. L-carnitine is essential for ?-oxidation of long-chain fatty acids in mitochondria, the activity of which is closely related to aging. Our results suggest that reduced carnitine biosynthesis capacity in MTKO mice compared to WT mice led to metabolic disorders of fatty acids in mitochondria in MTKO mice, which may have caused shortened lifespans.

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Longitudinal trajectories and determinants of human fungiform papillae density

Ajoy C. Karikkineth1, * , Eric Y. Tang2, * , Pei-lun Kuo3 , Luigi Ferrucci3 , Josephine M. Egan2 , Chee W. Chia2

doi : 10.18632/aging.203741

Volume 13, Issue 23, pp: 24989—25003

Tongue fungiform papillae contain taste buds crucial for taste and hormone-producing taste receptor cells; therefore, they may be considered as endocrine organs and have important age-associated physiological implications. We examine the cross-sectional and longitudinal trajectories of fungiform papillae density in 1084 participants from the Baltimore Longitudinal Study of Aging using linear regression models and mixed effects models. At baseline, the mean age was 67.86 ± 14.20 years, with a mean follow-up time among those with repeat visits of 4.24 ± 1.70 years. Women (53%) were younger (66.85 ± 13.78 vs. 69.04 ± 14.61 years, p < 0.001) and had a higher fungiform papillae density than men (16.14 ± 9.54 vs. 13.77 ± 8.61 papillae/cm2, p < 0.001). Whites (67%) had a lower fungiform papillae density than non-Whites after adjusting for age and sex. Factors cross-sectionally associated with a lower fungiform papillae density included a higher waist-hip ratio (? = ?8.525, p = 0.029), current smoking status (? = ?5.133, p = 0.014), and alcohol use within the past 12 months (? = ?1.571, p = 0.025). Longitudinally, fungiform papillae density decreased linearly with follow-up time (? = ?0.646, p < 0.001). The rate of decline was not affected by sex, race, BMI, waist-hip ratio, smoking, or alcohol use. The longitudinal decline of fungiform papillae density over time needs to be explored further in order to identify other possible age-associated physiological determinants.

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An efficient, non-invasive approach for in-vivo sampling of hair follicles: design and applications in monitoring DNA damage and aging

Natalie Kudlova1, * , Hanus Slavik1, * , Pavlina Duskova1 , Tomas Furst2 , Josef Srovnal1 , Jiri Bartek1,3,4 , Martin Mistrik1 , Marian Hajduch1

doi : 10.18632/aging.203744

Volume 13, Issue 23, pp: 25004—25024

In accordance with the 3 Rs principle (to replace, reduce and refine) animal models in biomedical research, we have developed and applied a new approach for sampling and analyzing hair follicles in various experimental settings. This involves use of a convenient device for non-invasive collection of hair follicles and processing methods that provide sufficient amounts of biological material to replace stressful and painful biopsies. Moreover, the main components of hair follicles are live cells of epithelial origin, which are highly relevant for most types of malignant tumors, so they provide opportunities for studying aging-related pathologies including cancer. Here, we report the successful use of the method to obtain mouse hair follicular cells for genotyping, quantitative PCR, and quantitative immunofluorescence. We present proof of concept data demonstrating its utility for routine genotyping and monitoring changes in quality and expression levels of selected proteins in mice after gamma irradiation and during natural or experimentally induced aging. We also performed pilot translation of animal experiments to human hair follicles irradiated ex vivo. Our results highlight the value of hair follicles as biological material for convenient in vivo sampling and processing in both translational research and routine applications, with a broad range of ethical and logistic advantages over currently used biopsy-based approaches.

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Serum levels of proinflammatory cytokines and selected bioelements in perimenopausal women with regard to body mass index

Anna Maria Cybulska1 , Kamila Rachubi?ska1 , Ma?gorzata Szkup1 , Daria Schneider-Matyka1 , Irena Baranowska-Bosiacka2 , Dariusz Chlubek2 , Anna Lubkowska3 , Mariusz Panczyk4 , Joanna So?ek-Pastuszka5 , El?bieta Grochans1

doi : 10.18632/aging.203754

Volume 13, Issue 23, pp: 25025—25037

During the menopause, decreased estrogen levels may be accompanied by increased levels of inflammatory mediators. Many studies also show significant relationships between the levels of bioelements and proinflammatory cytokines. The aim of this study was to assess the levels of proinflammatory cytokines, C-reactive protein (CRP), and selected bioelements in perimenopausal women with regard to BMI. Methods: The study of 217 perimenopausal women involved the completion of questionnaires concerning sociodemographic and medical data, anthropometric measurements, and blood collection. Results: In all studied women, the levels of IL-1? significantly positively correlated with Ca, Mg, and Sr; IFN? significantly negatively correlated with Sr, and IL-6 with Mg. In women with a normal BMI, the levels of IL-1? significantly positively correlated with Ca and Sr, and CRP positively correlated with Zn. In overweight women, the levels of IL-1? positively correlated with Ca, IL-6 with Na, and IFN? negatively correlated with Sr. In obese women, the levels of CRP positively correlated with Zn, TNF? with Mg, IFN? with Cu and P. The levels of IL-6 negatively correlated with Ca and Mg. Conclusions: BMI may be one of the factors that affect the relationship between serum bioelement levels and the levels of proinflammatory cytokines and CRP in women, especially during the menopausal period.

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Physical and functional measures predicting long-term mortality in community-dwelling older adults: a comparative evaluation in the Singapore Longitudinal Ageing Study

Chin Yee Cheong1 , Philip Yap1 , Xinyi Gwee2 , Denise Q.L. Chua2 , Shiou Liang Wee3 , Keng Bee Yap4 , Tze Pin Ng2

doi : 10.18632/aging.203756

Volume 13, Issue 23, pp: 25038—25054

Measures of functional status are known to predict mortality more strongly than traditional disease risk markers in old adult populations. Few studies have compared the predictive accuracy of physical and functional measures for long-term mortality. In this prospective cohort study, community-dwelling older adults (N = 2906) aged 55 + (mean age 66.6 ± 7.7 years) were followed up for mortality outcome up to 9 years (mean 5.8 years). Baseline assessments included Timed Up-and-Go (TUG), gait velocity (GV), knee extension strength, Performance Oriented Mobility Assessment, forced expiratory volume in 1 second, Mini-Mental State Examination (MMSE), Geriatric Depression Scale, frailty, and medical morbidity. A total of 111 (3.8%) participants died during 16976.7 person-years of follow up. TUG was significantly associated with mortality risk (HR = 2.60, 95% CI = 2.05–3.29 per SD increase; HR = 5.05, 95% CI = 3.27–7.80, for TUG score ? 9 s). In multivariate analysis, TUG remained significantly associated with mortality (HR = 1.64, 95% CI = 1.20–2.19 per SD increase; HR = 2.66, 95% CI = 1.67–4.23 for TUG score ? 9 s). In multivariable analyses, GV, MMSE, Frailty Index (FI) and physical frailty, diabetes and multi-morbidity were also significantly associated with mortality. However, TUG (AUC = 0.737) demonstrated significantly higher discriminatory accuracy than GV (AUC = 0.666, p < 0.001), MMSE (AUC = 0.63, p < 0.001), FI (AUC = 0.62, p < 0.001), physical frailty (AUC = 0.610, p < 0.001), diabetes (AUC = 0.582, p < 0.001) and multi-morbidity (AUC = 0.589, p < 0.001).

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IGFBP-6/sonic hedgehog/TLR4 signalling axis drives bone marrow fibrotic transformation in primary myelofibrosis

Lucia Longhitano1, * , Daniele Tibullo1, * , Nunzio Vicario1, * , Cesarina Giallongo2 , Enrico La Spina3 , Alessandra Romano3 , Sofia Lombardo4 , Marina Moretti5 , Francesco Masia5 , Anna Rita Daniela Coda6 , Santina Venuto6 , Paolo Fontana4 , Rosalba Parenti1 , Giovanni Li Volti1 , Michelino Di Rosa1 , Giuseppe A. Palumbo2, # , Arcangelo Liso6, #

doi : 10.18632/aging.203779

Volume 13, Issue 23, pp: 25055—25071

Primary myelofibrosis is a Ph-negative chronic myeloproliferative neoplasm characterized by bone marrow fibrosis and associated with the involvement of several pathways, in addition to bone marrow microenvironment alterations, mostly driven by the activation of the cytokine receptor/JAK2 pathway. Identification of driver mutations has led to the development of targeted therapy for myelofibrosis, contributing to reducing inflammation, although this currently does not translate into bone marrow fibrosis remission. Therefore, understanding the clear molecular cut underlying this pathology is now necessary to improve the clinical outcome of patients. The present study aims to investigate the involvement of IGFBP-6/sonic hedgehog /Toll-like receptor 4 axis in the microenvironment alterations of primary myelofibrosis. We observed a significant increase in IGFBP-6 expression levels in primary myelofibrosis patients, coupled with a reduction to near-normal levels in primary myelofibrosis patients with JAK2V617F mutation. We also found that both IGFBP-6 and purmorphamine, a SHH activator, were able to induce mesenchymal stromal cells differentiation with an up-regulation of cancer-associated fibroblasts markers. Furthermore, TLR4 signaling was also activated after IGFBP-6 and purmorphamine exposure and reverted by cyclopamine exposure, an inhibitor of the SHH pathway, confirming that SHH is involved in TLR4 activation and microenvironment alterations. In conclusion, our results suggest that the IGFBP-6/SHH/TLR4 axis is implicated in alterations of the primary myelofibrosis microenvironment and that IGFBP-6 may play a central role in activating SHH pathway during the fibrotic process.

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Construction and validation of a metabolic gene-associated prognostic model for cervical carcinoma and the role on tumor microenvironment and immunity

Jinzhi Huang1 , Fei Luo2 , Mingjie Shi2 , Jiaxin Luo3 , Choudi Ma3 , Shangzheng Li3 , Yue Wei4 , Runmin Guo2,5 , Ting Li6

doi : 10.18632/aging.203723

Volume 13, Issue 23, pp: 25072—25088

Metabolic reprogramming is a common feature of tumor cells and is associated with tumorigenesis and progression. In this study, a metabolic gene-associated prognostic model (MGPM) was constructed using multiple bioinformatics analysis methods in cervical carcinoma (CC) tissues from The Cancer Genome Atlas (TCGA) database, which comprised fifteen differentially expressed metabolic genes (DEMGs). Patients were divided into a high-risk group with shorter overall survival (OS) and a low-risk group with better survival. Receiver operating characteristic (ROC) curve analysis showed that the MGPM precisely predicted the 1-, 3- and 5-year survival of CC patients. As expected, MGPM exhibited a favorable prognostic significance in the training and testing datasets of TCGA. And the clinicopathological parameters including stage, tumor (T) and metastasis (M) classifications had significant differences in low- and high-risk groups, which further demonstrated the MGPM had a favorite prognostic prediction ability. Additionally, patients with low-ESTMATEScore had a shorter OS and when those combined with high-risk scores presented a worse prognosis. Through “CIBERSORT” package and Wilcoxon rank-sum test, patients in the high-risk group with a poor prognosis showed lower levels of infiltration of T cell CD8 (P < 0.001), T cells memory activated (P = 0.010) and mast cells resting (P < 0.001), and higher levels of mast cells activated (P < 0.001), and we also found these patients had a worse response for immunosuppressive therapy. These findings demonstrate that MGPM accurately predicts survival outcomes in CC patients, which will be helpful for further optimizing immunotherapies for cancer by reprogramming its cell metabolism.

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The isoflavone puerarin exerts anti-tumor activity in pancreatic ductal adenocarcinoma by suppressing mTOR-mediated glucose metabolism

Hengyue Zhu1,2 , Yanyi Xiao1 , Hangcheng Guo1 , Yangyang Guo1 , Youze Huang3 , Yunfeng Shan4 , Yongheng Bai1,5 , Xiangyang Lin2 , Hong Lu2

doi : 10.18632/aging.203725

Volume 13, Issue 23, pp: 25089—25105

Puerarin (8-(?-D-glucopyranosyl)-4?, 7-dihydroxyisoflavone), a natural flavonoid compound isolated from the traditional Chinese herb Radix puerariae, have been demonstrated has potential anti-tumor effects via induction of apoptosis and inhibition of proliferation. However, the effect and molecular mechanism of puerarin in pancreatic ductal adenocarcinoma (PDAC) remains unknown. In this study, the tumor-suppressive effects of puerarin were determined by both in-vitro and in-vivo assays. The effects of puerarin on the proliferation, apoptosis, migration and invasion of pancreatic cancer cells (PCCs), and tumor growth and metastasis in PDAC xenograft mouse model were performed. Puerarin treatment significantly repressed PCC proliferation. Puerarin induced the mitochondrial-dependent apoptosis of PCCs by causing a Bcl-2/Bax imbalance. Moreover, puerarin inhibited PCC migration and invasion by antagonizing epithelial-mesenchymal transition (EMT). In nude mouse model, PDAC growth and metastasis were reduced by puerarin administration. Mechanistically, puerarin exerted its therapeutic effects on PDAC by suppressing Akt/mTOR signaling. Importantly, puerarin bound to the kinase domain of mTOR protein, affecting the activity of the surrounding amino acid residues associated with the binding of the ATP-Mg2+ complex. Further studies showed that the inhibitory effects of puerarin on PCCs were abolished by a mTOR activator, indicating a crucial role of mTOR in anti-tumor effects of puerarin in PDAC. As a result, puerarin hindered glucose uptake and metabolism by downregulating the oxygen consumption rate (OCR) and the extracellular acidification rate (ECAR) dependent upon HIF-1? and glucose transporter GLUT1. Therefore, these findings indicated that puerarin has therapeutic potential for the treatment of PDAC by suppressing glucose uptake and metabolism via Akt/mTOR activity.

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Landscape of the oncogenic role of fatty acid synthase in human tumors

Xulei Huo1,2 , Lairong Song1,2 , Da Li1,2 , Ke Wang1,2 , Yali Wang3,4 , Feng Chen3,4 , Liwei Zhang1,2 , Liang Wang1,2 , Junting Zhang1,2 , Zhen Wu1,2

doi : 10.18632/aging.203730

Volume 13, Issue 23, pp: 25106—25137

Identifying a unique and common regulatory pathway that drives tumorigenesis in cancers is crucial to foster the development of effective treatments. However, a systematic analysis of fatty acid synthase across pan-cancers has not been carried out.

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LncRNA SNHG3 promotes gastric cancer cell proliferation and metastasis by regulating the miR-139-5p/MYB axis

Yan Xie1,2, * , Li Rong3, * , Min He1 , Yuyou Jiang1 , Haiyu Li4 , Li Mai5 , Fangzhou Song1

doi : 10.18632/aging.203732

Volume 13, Issue 23, pp: 25138—25152

The long non-coding RNA (lncRNA) SNHG3 has been shown to play oncogenic roles in several cancer types, but the mechanisms underlying its activity are poorly understood. In this study, we aimed to explore the clinical relevance and mechanistic role of SNHG3 in gastric cancer (GC). We found that SNHG3 expression in GC cell lines and tissues was significantly increased, and the upregulation of this lncRNA was correlated with tumor clinical stage and decreased patient survival. Knocking down SNHG3 in GC cells impaired the proliferative, migratory, and invasive activity in vitro and constrained in vivo GC xenograft tumor growth. Mechanistically, SNHG3 was found to bind and sequester miR-139-5p, thereby indirectly promoting the upregulation of the miR-139-5p target gene MYB. These data demonstrated that SNHG3 functions in an oncogenic manner to drive GC proliferation, migration, and invasion by regulating the miR-139-5p/MYB axis.

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A circadian rhythm-related gene signature associated with tumor immunity, cisplatin efficacy, and prognosis in bladder cancer

Ranran Zhou1,2 , Xinyu Chen1,2 , Jingjing Liang3 , Qi Chen1,2 , Hu Tian1,2 , Cheng Yang1,2 , Cundong Liu1,2

doi : 10.18632/aging.203733

Volume 13, Issue 23, pp: 25153—25179

Circadian dysregulation involves malignant tumor initiation and progression, but the understanding of circadian rhythm’s roles in bladder cancer (BCa) remains insufficient. The circadian rhythm-related genes were collected and clustered based on the Cancer Genome Atlas (TCGA), and the clustering was significantly associated with the prognosis and risk clinicopathological features. Through genomic difference analysis and gene pairing, a circadian rhythm-related signature was successfully established. Kaplan-Meier survival analysis and time-dependent receiver operating curves displayed that the prognosis model was a reliable prognosis biomarker both in the training cohort (n = 396, P = 2.687e-10) and external validation cohort (n = 224, P = 1.45e-02). The patients with high risk have high immune infiltration and high expression of immune checkpoint genes, which partly account for the poor prognosis. TIDE algorithm and the validation in IMvigor210 cohort indicated that the risk signature was a promising marker for the immunotherapeutic response. The risk model could also predict the therapeutic response of cisplatin, which was validated in the Genomics of Drug Sensitivity in Cancer database (P = 0.0049), TCGA (P = 0.038), and T24 BCa cells treated with cisplatin. The functional enrichment showed the risk model was significantly correlated with some malignant phenotypes, such as angiogenesis, epithelial-mesenchymal transition, and KRAS signaling pathway. Totally, we proposed a novel circadian rhythm-related signature for prognosis evaluation, which also helped to predict the immune infiltration and cisplatin sensitivity in BCa.

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Licochalcone A activation of glycolysis pathway has an anti-aging effect on human adipose stem cells

Yating Wu1, * , Hao Wang2, * , Jianbo Zhu1 , Haitao Shen1 , Hailiang Liu1,2

doi : 10.18632/aging.203734

Volume 13, Issue 23, pp: 25180—25194

Licochalcone A (LA) is a chalcone flavonoid of Glycyrrhiza inflata, which has anti-cancer, antioxidant, anti-inflammatory, and neuroprotective effects. However, no anti-aging benefits of LA have been demonstrated in vitro or in vivo. In this study, we explored whether LA has an anti-aging effect in adipose-derived stem cells (ADSCs). We performed ?-galactosidase staining and measured reactive oxygen species, relative telomere lengths, and P16ink4a mRNA expression. Osteogenesis was assessed by Alizarin Red staining and adipogenesis by was assessed Oil Red O staining. Protein levels of related markers runt-related transcription factor 2 and lipoprotein lipase were also examined. RNA sequencing and measurement of glycolysis activities showed that LA significantly activated glycolysis in ADSCs. Together, our data strongly suggest that the LA have an anti-aging effect through activate the glycolysis pathway.

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YY1 and eIF4A3 are mediators of the cell proliferation, migration and invasion in cholangiocarcinoma promoted by circ-ZNF609 by targeting miR-432-5p to regulate LRRC1

Canghai Guan1, * , Lang Liu1, * , Yuqiao Zhao1, * , Xianhe Zhang1 , Guanglin Liu1 , Haicun Wang1 , Xin Gao1 , Xiangyu Zhong1 , Xingming Jiang1

doi : 10.18632/aging.203735

Volume 13, Issue 23, pp: 25195—25212

Cholangiocarcinoma is a highly aggressive malignant tumor, and its incidence is increasing all over the world. More and more evidences show that the aberrant expression of circular RNAs play important roles in tumorigenesis and progression. Current studies on the expression and function of circRNAs in cholangiocarcinoma are scarce. In this study, circ-ZNF609 was discovered as a novel circRNA highly expressed in cholangiocarcinoma for the first time. The circ-ZNF609 expression is connected with the advanced TNM stage, lymphatic invasion and survival time in cholangiocarcinoma patients, and can be used as an independent prognostic factor for the patients. Circ-ZNF609 can promote the cholangiocarcinoma cells proliferation, migration and invasion in vitro, it can also catalyze the xenograft growth in vivo. The promoting effect of circ-ZNF609 on cholangiocarcinoma is achieved via oncogene LRRC1 up-regulation through targeting miR-432-5p by endogenous competitive RNA mechanism. In addition, transcription factor YY1 can bind to the promoter of ZNF609 to further facilitate the transcription of circ-ZNF609. RNA binding protein eIF4A3 can bind to the pre-mRNA of circ-ZNF609 which promotes the circ-ZNF609 circular formation. Overall, YY1/eIF4A3/circ-ZNF609/miR-432-5p/LRRC1 have a significant role in progression of cholangiocarcinoma, and circ-ZNF609 is expected to become a novel biomarker for targeted therapy and prognosis evaluation of cholangiocarcinoma.

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hsa_circ_0072389, hsa_circ_0072386, hsa_circ_0008621, hsa_circ_0072387, and hsa_circ_0072391 aggravate glioma via miR-338-5p/IKBIP

Jian Liang1 , Xing Li3 , Jian Xu2 , Guang-Mou Cai1 , Jian-Xuan Cao1 , Bo Zhang1

doi : 10.18632/aging.203740

Volume 13, Issue 23, pp: 25213—25240

Glioma is a primary intracranial tumor with high morbidity and mortality. We acquired miR-338-5p, which suppresses the development of glioma, from the GEO and CGGA databases. In addition, we predicted that hsa_circ_0072389, hsa_circ_0072386, hsa_circ_0008621, hsa_circ_0072387, and hsa_circ_0072391 could relieve the silencing of IKBIP by miR-338-5p. By analyzing genes related to IKBIP expression, possible pathways affecting glioma were identified. This study provides new ideas for investigating multiple circRNAs in ceRNAs.

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Endothelial cell–derived exosomal circHIPK3 promotes the proliferation of vascular smooth muscle cells induced by high glucose via the miR-106a-5p/Foxo1/Vcam1 pathway

Shaohua Wang1 , Min Shi1 , Jiao Li1 , Yuanyuan Zhang1 , Wenjing Wang1 , Peixin Xu1 , Yongjun Li1

doi : 10.18632/aging.203742

Volume 13, Issue 23, pp: 25241—25255

The abnormal proliferation of vascular smooth muscle cells (VSMCs) plays an important role in the development and progression of diabetic vascular complications. In high-glucose (HG) conditions, endothelial cells (ECs) act as the first barrier to damaging stimuli and trigger a multi-response, including EC and VSMC crosstalk. However, the crosstalk pathways between ECs and VSMCs under HG conditions remain unclear. This study aimed to explore the roles and underlying mechanism of exosomes derived from ECs in the crosstalk between ECs and VSMCs. Our results showed that mouse aortic endothelial cell (MAEC)–secreted exosomes could promote the proliferation and inhibit the apoptosis of VSMCs induced by HG. Furthermore, we isolated the exosomes secreted by MAECs and found that exosomes derived from MAECs that were exposed to HG could transfer circHIPK3, which is enriched in MAEC-derived exosomes, to VSMCs. Exosomal circHIPK3 promoted the proliferation and inhibited the apoptosis of VSMCs. circHIPK3 sponged miR-106a-5p to relieve its repression of forkhead box O1 (Foxo1) expression. The increased expression of Foxo1 acted as a transcription factor to promote Vcam1 expression, thus facilitating the uptake of MAEC-derived exosomes by VSMCs. The results of this study suggested that exosomal circHIPK3 derived from MAECs promotes the proliferation of VSMCs induced by HG via the miR-106a-5p/Foxo1/Vcam1 pathway.

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MicroRNA therapy confers anti-senescent effects on doxorubicin-related cardiotoxicity by intracellular and paracrine signaling

Wenzheng Xia1,2, * , Bowen Chang3, * , Liqun Li2 , Tingting Hu4 , Jiaqi Ye4 , Hanbin Chen4 , Wenfeng Li4 , Tao Zan1, * , Meng Hou4, *,&

doi : 10.18632/aging.203743

Volume 13, Issue 23, pp: 25256—25270

Doxorubicin (Dox), an important anthracycline, is a potent anticancer agent that is used for treating solid tumors and hematologic malignancies. However, its clinical use is hampered by cardiac cardiotoxicity. This study aimed to investigate the cardioprotective potential of miR-199a-3p. Continuous Dox treatment not only markedly induced cardiomyocyte senescence but also resulted in a growing number of senescence-associated secretory phenotype (SASP) cardiomyocytes, frequently leading to heart senescence. This study showed that miR-199a-3p was downregulated in cardiomyocytes when exposed to Dox. The cardiac-specific overexpression of miR-199a-3p promoted cell cycle re-entry and cell proliferation, resulting in relief from cardiac senescence. Also, the elevation of miR-199a-3p inhibited the generation of SASP, thus, hampering the spread of senescence. In cardiomyocytes, the modulation of miR-199a-3p changed the levels of senescence-related protein GATA4. The ectopic expression of GATA4 blunted the anti-senescence effect of miR-199a-3p. Together, the data supported a role for miR-199a-3p during Dox cardiotoxicity. The elevation of miR-199a-3p might provide a dual therapeutic advantage in Dox cardiotoxicity therapy by simultaneously preventing cardiac senescence and reducing the spread of senescence.

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An integrative pan-cancer analysis reveals the oncogenic role of mutS homolog 6 (MSH6) in human tumors

Haibo Zhan1,2 , Fengbo Mo1,2 , Qiang Xu1,2 , Song Wang1,2 , Bin Zhang1,2 , Xuqiang Liu1,2 , Min Dai1,2 , Hucheng Liu1,2

doi : 10.18632/aging.203745

Volume 13, Issue 23, pp: 25271—25290

There are three most important mismatch repair genes in the mismatch repair system, MSH6 is one of them and it plays an essential role in DNA mismatch repair. Several emerging cell- or animal-based studies have verified that MSH6 mutations are closely linked to the occurrence, progression or metastasis of cancer, but there is still no practicable pan-cancer analysis. On account of the available datasets of the cancer genome atlas (TCGA) and Gene expression omnibus (GEO), a comprehensive analysis of the potential carcinogenic effects of the MSH6 gene was conducted in 33 human cancers. MSH6 was highly expressed in most cancers, and the high expression of MSH6 was associated with poor overall survival prognosis of patients with multiple cancers, such as adrenocortical carcinoma. MSH6 mutations occurred in most cancers and were closely related to the prognosis of cancer patients. Increased phosphorylation levels of S227 and S830 were noted in several tumors, including breast cancer and colon cancer. MSH6 expression was also observed to be correlated with cancer-associated fibroblasts and CD8+ T-cells infiltration levels in various cancer types, e. g. pancreatic adenocarcinoma or testicular germ cell tumors. Furthermore, pathway enrichment analysis demonstrated that the main biological activities of MSH6 were related to ATPase activity, mismatch repair, and DNA metabolism-related functions. Altogether, our pan-cancer research has suggested that the MSH6 expression level was closely related to the carcinogenesis and prognosis of certain tumors, which helps to know the effect of MSH6 in tumorigenesis from the point of view of clinical tumor samples.

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Sorbitol accumulation decreases oocyte quality in aged mice by altering the intracellular redox balance

Yuexin Zhang1, * , Zhengjie Yan1, * , Hanwen Liu1 , Lingjun Li1 , Chun Yuan1 , Lianju Qin1 , Lingbo Cai1 , Jiayin Liu1 , Yanqiu Hu1 , Yugui Cui1

doi : 10.18632/aging.203747

Volume 13, Issue 23, pp: 25291—25303

Sorbitol is a product of glucose metabolism through the polyol pathway. Many studies have demonstrated that excessive sorbitol can disrupt the intracellular redox balance. However, we still know very little about the impact of excessive intracellular sorbitol on oocyte quality, oocyte maturation, and embryo developmental potential. This study explored whether intracellular sorbitol accumulates in the oocytes of aged mice during in vitro maturation (IVM) and what roles sorbitol plays in oocyte development and maturation. Our results showed that sorbitol levels were significantly higher in in vitro-matured oocytes from aged mice than in oocytes from young mice (14.08 ± 3.78 vs. 0.23 ± 0.04 ng/oocyte). The expression of aldose reductase (AR) mRNA was significantly higher in the in vitro-cultured oocytes from 9-month-old mice than prior to culture. To decrease the excessive intracellular sorbitol in oocytes from aged mice, sorbinil, a specific inhibitor of aldose reductase, was supplemented in IVM medium, and the sorbitol level was significantly decreased (14.08 ± 3.78 vs. 0.48 ± 0.19 ng/oocyte). Our results indicated that the percentage of oocytes with first polar body extrusion (PBE) was significantly higher in the sorbinil group than in the aged group (82.4% ± 7.2% vs. 66.1% ± 6.9%), and the content of sorbitol was drastically increased in the aged group. The ROS fluorescence intensity in the sorbinil group was drastically lower than that in the aged group, while the GSH fluorescence intensity was significantly higher. Interestingly, SOD1 was upregulated in the sorbinil group. The present study suggests that excessive sorbitol accumulation is induced during IVM in aged mouse oocytes, which negatively influences oocyte quality by altering the intracellular redox balance. Inhibition of sorbitol accumulation may be a potential method to improve the nuclear maturation of aged oocytes.

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GDI2 is a novel diagnostic and prognostic biomarker in hepatocellular carcinoma

Wen Zhang1,2 , Zhongjian Liu2 , Shilin Xia3 , Lei Yao4 , Lan Li5 , Ziying Gan2 , Hui Tang2 , Qiang Guo2 , Xinmin Yan2 , Zhiwei Sun1,2

doi : 10.18632/aging.203748

Volume 13, Issue 23, pp: 25304—25324

GDP Dissociation inhibitor 2 (GDI2) gene has been correlated with some important biological processes in a variety of cancers, whereas the role of GDI2 in hepatocellular carcinoma (HCC) is ill-defined. We aimed to demonstrate the relationship between GDI2 and HCC based on The Cancer Genome Atlas (TCGA) data mining.

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Artesunate treatment ameliorates ultraviolet irradiation-driven skin photoaging via increasing ?-catenin expression

Liming Tian1, * , Dan Ke2, * , Yi Hong3 , Chong Zhang4 , Daizhi Tian4 , Long Chen1 , Lirui Zhan1 , Shiqin Zong1

doi : 10.18632/aging.203749

Volume 13, Issue 23, pp: 25325—25341

Artesunate, a semi-synthetic derivative of artemisinin, exerts various pharmacological activities. Nevertheless, the effects of Art on skin photoaging remain unclear. Herein, we investigated whether Art ameliorated ultraviolet-irradiated skin photoaging in HaCaT cells and mice.

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Protective effects of galangin against H2O2/UVB-induced dermal fibroblast collagen degradation via hsa-microRNA-4535-mediated TGF?/Smad signaling

Jian-Jr Lee1,2 , Shang-Chuan Ng3,4 , Yean-Tin Ni3,4 , Jian-Sheng Liu3,5 , Chih-Jung Chen6 , Viswanadha Vijaya Padma7 , Chih-Yang Huang8,9,10,11,12, * , Wei-Wen Kuo3,4, *

doi : 10.18632/aging.203750

Volume 13, Issue 23, pp: 25342—25364

This study aimed to investigate the mechanism underlying the protective effects of galangin against H2O2/UVB-induced damage using in vitro and in vivo models of photodamage. Moreover, we identified the involvement of miRNA regulation in this process. The H2O2/UVB-treated HS68 human dermal fibroblasts and UVB-induced C57BL/6J nude mice were used as in vitro and in vivo models of photodamage. The results showed that galangin treatment alleviated H2O2/UVB-induced reduction in cell viability, TGF?/Smad signaling impairment, and dermal aging. Based on the results of microRNA array analyses and database searches, hsa-miR-4535 was identified as a potential candidate miRNA that targets Smad4. In vitro, galangin treatment activated Smad2/3/4 complex and inhibited hsa-miR-4535 expression in H2O2/UVB-exposed cells. In vivo, topical application of low (12 mg/kg) and high doses (24 mg/kg) of galangin to the dorsal skin of C57BL/6J nude mice significantly alleviated UVB-induced skin photodamage by promoting TGF?/Smad collagen synthesis signaling, reducing epidermal hyperplasia, wrinkle formation, and skin senescence, as well as inhibiting hsa-miR-4535 expression. Taken together, our findings indicate a link between hsa-miR-4535 and TGF?/Smad collagen synthesis signaling and suggest these factors to be involved in the photo-protective mechanism of galangin in dermal fibroblasts against H2O2/UVB-induced aging. The evidence indicated that galangin with anti-aging properties can be considered as a supplement in skin care products.

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Anemoside B4 sensitizes human colorectal cancer to fluorouracil-based chemotherapy through src-mediated cell apoptosis

Xing He1 , Jun Tang1 , He-Zhong Yan1 , Jiao-Xue Wang1 , Hai-Qing Li1 , Xiao-Wei Duan1 , Sen-Yuan Yu1 , Xi-Lu Hou1 , Guo-Bin Liao1 , Wei Liu1

doi : 10.18632/aging.203751

Volume 13, Issue 23, pp: 25365—25376

Currently, 5-Fluorouracil (5-FU) based chemotherapy is the primary option for colorectal cancer after surgery, whereas chemotherapy resistance related mortality is observed in a large proportion of patients. Anemoside B4 (AB4) is a triterpene saponin, which exhibits a considerable activity in oncotherapy. In this study, we explored the efficacy of AB4 in FU-based chemotherapy in colorectal cancer cells and the underlying molecular mechanisms. Our results indicated a significant synergistic activity of AB4 in 5-FU treated colorectal cancer cells. Furthermore, AB4 treatment eliminated colorectal cancer stem cells by promoting apoptotic cell death in 5-FU resistant colorectal cancer cells. Mechanically, AB4 activated caspase-9 pathway in 5-FU resistant colorectal cancer cells. Elevated Src activity induced cell apoptosis and cancer stem cells elimination effects in AB4 treated colorectal cancer cells. In conclusion, AB4 showed promising sensitization effect in the FU-based chemotherapy of colorectal cancer. Our study may pave a way to ameliorate FU-based chemotherapeutic efficiency in colorectal cancer.

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Tartary buckwheat flavonoids relieve the tendency of mammary fibrosis induced by HFD during pregnancy and lactation

Xingchi Kan1, * , Juxiong Liu1, * , Xiangyu Cai1 , Yaping Huang1 , Ping Xu1 , Shoupeng Fu1 , Wenjin Guo1 , Guiqiu Hu1

doi : 10.18632/aging.203752

Volume 13, Issue 23, pp: 25377—25392

Mammary gland fibrosis is a chronic and irreversible disease. Tartary buckwheat flavonoids (TBF) are a natural product of flavonoid extracts from buckwheat and have a wide range of biological activities. The purpose of this experiment was to explore whether HFD during pregnancy and lactation induces fibrosis of the mammary tissue and whether TBF alleviates the damage caused by HFD, along with its underlying mechanism. The HFD significantly increased the levels of TNF-?, IL-6, IL-1?, and MPO; significantly damaged the integrity of the blood-milk barrier; significantly increased the levels of collagen 1, vimentin and ?-SMA, and reduced the level of E-cadherin. However, these effects were alleviated by TBF. Mechanistic studies showed that TBF inhibited the activation of AKT/NF-?B signaling and predicted the AKT amino acid residues that formed hydrogen bonds with TBF; in addition, these studies not only revealed that TBF promoted the expression of the tight junction proteins (TJs) claudin-3, occludin and ZO-1 and inhibited the activation of TGF-?/Smad signaling but also predicted the Smad MH2 amino acid residues that formed hydrogen bonds with TBF. Conclusion: HFD consumption during pregnancy and lactation induced the tendency of mammary fibrosis. TBF alleviated the tendency of mammary fibrosis by inhibiting the activation of AKT/NF-?B, repairing the blood-milk barrier and inhibiting the activation of TGF-?/Smad signaling.

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Functional rare variant in a C/EBP beta binding site in NINJ2 gene increases the risk of coronary artery disease

Pengyun Wang1, * , Yifan Wang2, * , Huixin Peng2, * , Jingjing Wang3 , Qian Zheng2 , Pengxia Wang2 , Jing Wang2 , Hongfu Zhang2 , Yufeng Huang4 , Liang Xiong1 , Rongfeng Zhang5 , Yunlong Xia5 , Qing K. Wang2 , Chengqi Xu2

doi : 10.18632/aging.203755

Volume 13, Issue 23, pp: 25393—25407

NINJ2 regulates activation of vascular endothelial cells, and genome-wide association studies showed that variants in NINJ2 confer risk to stroke. However, whether variants in NINJ2 are associated with coronary artery disease (CAD) is unknown.

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lncRNA CASC7 regulates pathological progression of ox-LDL-stimulated atherosclerotic cell models via sponging miR-21 and regulating PI3K/Akt and TLR4/NF-?B signaling pathways

Xueliang Pei1 , Yongjin Wen1 , Facai Cui2 , Zhiyuan Yang1 , Zhouliang Xie1

doi : 10.18632/aging.203757

Volume 13, Issue 23, pp: 25408—25425

Atherosclerosis (AS) is a frequently occurring cause of cardiovascular disease and involves a complicated pathophysiological process. Studies suggest that long non-coding RNAs (lncRNAs) are involved in AS genesis and progression, but mechanisms underlying these connections are unclear. Therefore, this work focused on exploring the role of lncRNA CASC7 in AS. In this study, RNA-seq sequencing results identified 1040 lncRNAs differentially expressed between AS patients and healthy controls. Of these lncRNAs, 458 were up-regulated and 582 were downregulated. CASC7 was found to be down-regulated in serum samples from AS patients and in HUVEC and VSMC exposed to ox-LDL. Overexpression of CASC7 inhibited proliferation and enhanced apoptosis of VSMC, and it markedly reduced IL-1?, IL-6 and TNF-? levels in HUVEC. Increased expression of a CASC7 target, miR-21, abolished the effects of CASC7 on HUVEC and VSMC. Notably, miR-21 targets PI3K in VSMC and TLR4 in HUVEC. The inhibitory effect of CASC7 was decreased by stimulation of PI3K, suggesting that the CASC7/miR-21 axis functions through PI3K/Akt signaling in VSMC. Similarly, the inhibitory effect of CASC7 on the inflammatory response in HUVEC was abolished through activating the TLR4/NF-?B signaling pathway. CASC7 inhibited proliferation and enhanced the apoptosis of VSMC through modulating the miR-21/PI3K-AKT axis, and upregulating CASC7 suppressed the inflammatory response of HUVEC by sponging miR-21 to inhibit the TLR4/NF-?B signal pathway.

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YTHDC1 gene polymorphisms and neuroblastoma susceptibility in Chinese children

Yong Li1,2 , Tongyi Lu3 , Jian Wang1 , Zhenjian Zhuo3 , Lei Miao3 , Zhonghua Yang4 , Jiao Zhang5 , Jiwen Cheng6 , Haixia Zhou7 , Suhong Li8 , Li Li9 , Jing He3 , Aiwu Li1

doi : 10.18632/aging.203760

Volume 13, Issue 23, pp: 25426—25439

Neuroblastoma (NB) is the most common extracranial tumor in children. YTHDC1, a member of RNA methylation modification binding proteins, plays critical roles in tumor occurrence and metastasis. However, it is unclear whether YTHDC1 gene polymorphisms are related to NB susceptibility. Herein, we aimed to evaluate the association between YTHDC1 gene polymorphisms (rs2293596 T>C, rs2293595 T>C, rs3813832 T>C) and susceptibility of NB by logistic regression models. In this eight-center case-control study, 898 patients with NB and 1734 healthy controls were genotyped by TaqMan assay. The results showed that rs3813832 TC genotype could significantly reduce the susceptibility of NB compared with the TT genotype [adjusted odds ratio (AOR) = 0.81, 95% confidence interval (CI) = 0.68–0.96, P = 0.018]. Combined genotype analysis revealed that individuals with 3 protective genotypes had a prominently lower NB risk than those with 0-2 protective genotypes (AOR = 0.80, 95% CI = 0.68–0.94, P = 0.006). The stratified analysis also demonstrated the protective effect of rs3813832 TC/CC and 3 protective genotypes in certain subgroups. Further functional experiments revealed that YTHDC1 siRNA-554, targeting the area near the rs3813832 T>C polymorphism site, could observably inhibit the proliferation and migration of NB cells. In conclusion, our findings highlight the involvement of YTHDC1 gene and its genetic variants in the etiology of NB.

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Titanium dioxide nanoparticles perturb the blood-testis barrier via disruption of actin-based cell adhesive function

Dong-Qi Ni2,4,5, * , Dan-Dan Ma2, * , Shuang-Li Hao2, * , Wan-Xi Yang2 , Tamas Kovacs3 , Fu-Qing Tan1

doi : 10.18632/aging.203763

Volume 13, Issue 23, pp: 25440—25452

As one of the most commonly used nanoparticles, titanium dioxide nanoparticles (TiO2-NPs) are widely used as coating reagents in cosmetics, medicine and other industries. The increasing risk of exposure to TiO2-NPs raises concerns about their safety. In this study, we investigated the mechanism by which TiO2-NPs cross the blood-testis barrier (BTB). TM-4 cells were selected as an in vitro Sertoli cell model of BTB. Cell viability, cell morphological changes, apoptosis, oxidative damage, and the expression levels of actin regulatory and tight junction (TJ) proteins were assessed in TM-4 cells treated with 3-nm and 24-nm TiO2-NPs. Cells treated with 3-nm TiO2-NPs exhibited increased cytotoxicity and decreased Annexin II expression, whereas cells treated with 24-nm TiO2-NPs exhibited increased Arp 3 and c-Src expression. Both TiO2-NPs induced significant oxidative stress, decreased the expression of TJ proteins (occludin, ZO-1 and claudin 5), damaged the TJ structure, and exhibited enlarged gaps between TM-4 cells. Our results indicated that both TiO2-NPs crossed the BTB by disrupting actin-based adhesive junctions of TM-4 cells; however, apoptosis was not observed. Our results provide new insights into how TiO2-NPs cross the BTB.

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A risk model based on autophagy-related lncRNAs for predicting prognosis and efficacy of immunotherapy and chemotherapy in gastric cancer patients

Lei Gao1 , Juan Xue2 , Xiaomin Liu1 , Lei Cao1 , Ruifang Wang1 , Liangliang Lei3

doi : 10.18632/aging.203765

Volume 13, Issue 23, pp: 25453—25465

Long non-coding RNAs (lncRNAs) are a class of non-protein-coding RNAs essential to the occurrence and development of gastric cancer (GC). We aimed to identify critical lncRNA pairs to construct a prognostic model and assess its performances in prognosis and efficacy prediction in GC patients receiving immunotherapy and chemotherapy. We searched transcriptome and clinical data of GC patients from The Cancer Genome Atlas (TCGA) database. Autophagy-related lncRNAs were identified using co-expression network analysis, and lncRNA pairs with prognostic value were selected using pairwise transcriptome analysis. The gene pairs were subjected to LASSO algorithm for identification of optimal gene pairs for risk model construction. Patients were classified into the low-risk and high-risk groups with the RiskScore as a cutoff. Finally, 9 optimal gene pairs were identified in the LASSO algorithm model for construction of a lncRNA prognostic risk model. For predictive performances, it successfully predicted a shorter survival of high-risk patients than that obtained in low-risk individuals (P < 0.001). It showed moderate AUC (area under the curve) values for 1-, 2-, and 3-year overall survival prediction of 0.713 and could serve as an independent predictor for GC prognosis. Compared to the low-risk group, high-risk patients had higher expressions of marker genes for immune checkpoint inhibitors (ICIs) and showed higher sensitivity to the chemotherapy agents, rapamycin, bexarotene, and bicalutamide. Our findings demonstrate a robust prognostic model based on nine autophagy-related lncRNA pairs for GC. It acts as an independent predictor for survival and efficacy prediction of immunotherapy and chemotherapy in GC patients.

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Prognostic value of CDCA3 in kidney renal papillary cell carcinoma

Hao Li1 , Mi Li1 , Caihong Yang1 , Fengjing Guo1 , Sisi Deng3 , Lixi Li2 , Tian Ma1 , Jiyuan Yan1 , Hua Wu1 , Xiaojuan Li2

doi : 10.18632/aging.203767

Volume 13, Issue 23, pp: 25466—25483

Kidney renal papillary cell carcinoma (KIRP) is a type of low-grade malignant renal cell carcinoma. Huge challenges remain in the treatment of KIRP. Cell division cycle associated 3 (CDCA3) participates in human physiological and pathological processes. However, its role in KIRP has not been established. Here, we evaluated the prognostic value of CDCA3 in KIRP using a comprehensive bioinformatics approach. Data for CDCA3 expression in KIRP were obtained from online database. Different expression genes between high and low CDCA3 expression groups were identified and evaluated by performing Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. A gene set enrichment analysis was performed to elucidate the function and pathway differences between the different. Differences in immune cell infiltration between low and high CDCA3 expression groups were analyzed by a single-sample GSEA method for immune cells. A protein-protein interaction network was generated and hub genes were identified. UALCAN was used to analyze associations between the mRNA expression levels of CDCA3 in KIRP tissues with clinicopathologic parameters. The diagnostic efficacy of CDCA3 for KIRP was analyzed by ROC analysis. Logistic regression was used to analyze relationships between the clinicopathological characteristics and CDCA3 expression. Our results indicated that high CDCA3 mRNA expression is significantly associated with some clinicopathologic parameters in KIRP patients High CDCA3 mRNA expression associated with a shorter overall survival, progression-free interval, and disease-special survival. Taken together, CDCA3 is a potential target for the development of anti-KIRP therapeutics and is an efficient prognostic marker.

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Hsa_circ_0008259 modulates miR-21-5p and PDCD4 expression to restrain osteosarcoma progression

Kai Guan1 , Shizhang Liu2 , Keke Duan2 , Xiaoxia Zhang2 , Huitong Liu2 , Bingqiang Xu2 , Xi Wang2 , Xin Jin1, &

doi : 10.18632/aging.203769

Volume 13, Issue 23, pp: 25484—25495

Osteosarcoma (OS) is one of the most common primary bone tumors in children and adolescents. However, the molecular mechanism of OS tumorigenesis is still little known. Circular RNA (circRNA) is a key player in the progression of many cancers. This study is performed to decipher the role and mechanism of circ_0008259 in the progression of OS.

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A novel 6-gene signature derived from tumor-infiltrating T cells and neutrophils predicts survival of bladder urothelial carcinoma

Xuan Zou1,2, * , Yong Wei3, * , Tao Qi4, * , Xiaping Wang5, * , Wenren Zuo3 , Tongshan Wang6 , Wei Zhu6 , Xin Zhou6

doi : 10.18632/aging.203770

Volume 13, Issue 23, pp: 25496—25517

Intratumoral immune cells were reported to be associated with prognosis of bladder urothelial carcinoma (BUC). However, the role of immune cells related genes in BUC prognosis is less well defined. In the study, we analyzed data retrieved from the Cancer Genome Atlas database and found higher neutrophils and lower T cells infiltration in BUC tumor tissues were significantly correlated with patients’ worse prognosis. Additionally, the expression levels of 164 genes were significantly correlated with T cells and neutrophils proportions. A Cox proportional-hazards model integrating 6 genes expression (EMP1, RASGRP4, HSPA1L, AHNAK, SLC1A6, and PRSS8) was identified. The 6-gene signature outperformed other clinical factors in risk prediction and was an independent prognostic factor for BUC. The findings were further conformed in three Gene Expression Omnibus datasets (n=331) and Jiangsu Province Hospital cohort (n = 46). Gene set enrichment analysis revealed that the model was highly involved in some immune-related pathways. A comprehensive nomogram combining the model and other clinical parameters was finally constructed to facilitate clinical application. In conclusion, a T cell and neutrophil-associated 6-gene prognostic model was identified for the survival prediction of BUC patients.

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Identification of a novel immune signature for optimizing prognosis and treatment prediction in colorectal cancer

Yan Li1, * , Yiyi Li1, * , Zijin Xia1, * , Dun Zhang2,3 , Xiaomei Chen4 , Xinyu Wang1 , Jing Liao5 , Wei Yi6 , Jun Chen1,7,8,9,10

doi : 10.18632/aging.203771

Volume 13, Issue 23, pp: 25518—25549

Globally, colorectal cancer (CRC) is one of the most lethal malignant diseases. However, the currently approved therapeutic options for CRC failed to acquire satisfactory treatment efficacy. Tailoring therapeutic strategies for CRC individuals can provide new insights into personalized prediction approaches and thus maximize clinical benefits.

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A novel immune-related long non-coding RNAs risk model for prognosis assessment of lung adenocarcinoma

Songmei Lu1 , Nan Shan2 , Xingyue Chen1 , Fangliang Peng2 , Yiming Wang1 , Hao Long3

doi : 10.18632/aging.203772

Volume 13, Issue 23, pp: 25550—25563

The abundant immune-related long non-coding RNA (IRLNRs) in immune cells and immune microenvironment have the potential to forecast prognosis and evaluate the effect of immunotherapy. IRLNRs analysis will provide a new perspective for LUAC research.

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CHIP ameliorates cerebral ischemia-reperfusion injury by attenuating necroptosis and inflammation

Dabao Yao1,2, * , Shuo Zhang1,2, * , Zhengwei Hu1,2 , Haiyang Luo1,2 , Chengyuan Mao1,2 , Yu Fan1,2 , Mibo Tang1,2 , Fen Liu1,2 , Si Shen1,2 , Liyuan Fan1,2 , Mengjie Li1,2 , Jingjing Shi1,2 , Jiadi Li1,2 , Dongrui Ma1,2 , Yuming Xu1,2,3 , Changhe Shi1,2,3, &

doi : 10.18632/aging.203774

Volume 13, Issue 23, pp: 25564—25577

Blood reperfusion of ischemic cerebral tissue may cause cerebral ischemia-reperfusion (CIR) injury. Necroptosis and inflammation have been demonstrated to be involved in the disease-related process of CIR injury. The E3 ubiquitin ligase carboxyl terminus of Hsp70-interacting protein (CHIP) can modulate multiple cellular signaling processes, including necroptosis and inflammation. Numerous studies have demonstrated the neuroprotective effects of CHIP on multiple central nervous system (CNS) diseases. However, the effects of CHIP on CIR injury have not been fully explored. We hypothesize that CHIP can exert neuroprotective effects by attenuating necroptosis and inflammation during CIR injury. In the present study, adult wild-type (WT) C57BL/6 mice and CHIP knock-in (KI) mice with a C57BL/6 background and CHIP overexpression in neural tissue underwent middle cerebral artery occlusion (MCAO) surgery to simulate CIR onset. Our data indicated that CHIP expression in the peri-infarct tissue was markedly increased after MCAO surgery. Compared with WT mice, CHIP KI mice significantly improved neurological deficit scores, decreased cerebral infarct volume, and attenuated brain edema and neuronal damage. Meanwhile, CHIP overexpression attenuated necroptosis and inflammation induced by MCAO surgery. These findings indicated that overexpression of CHIP might exert neuroprotective effects by attenuating necroptosis and inflammation during CIR injury, and increasing CHIP levels may be a potential strategy in cerebrovascular disease therapy.

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G-Quadruplexes and the DNA/RNA helicase DHX36 in health, disease, and aging

Aaron Antcliff1 , Louise D. McCullough1,2 , Andrey S. Tsvetkov1,2,3

doi : 10.18632/aging.203738

Volume 13, Issue 23, pp: 25578—25587

G-Quadruplex (G4) DNA (G4 DNA) and RNA (G4 RNA) are secondary nucleic acid structures that have multiple roles in vital cellular processes. G4 DNA- and RNA-binding proteins and unwinding helicases associate with and regulate G4s during virtually all processes that involve DNA and RNA. DEAH-Box helicase 36 (DHX36), a member of the large DExD/H box helicase family, enzymatically unwinds both G4 DNA and G4 RNA. By exerting its G4 helicase function, DHX36 regulates transcription, genomic stability, telomere maintenance, translation and RNA metabolism. This review will provide an overview of G4s and DHX36, including DHX36’s potential role in neuronal development and neurodegeneration. We conclude with a discussion of the possible functions of G4s and DHX36 in the aging brain.

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Influence of early life stress on depression: from the perspective of neuroendocrine to the participation of gut microbiota

Xi Tan1 , Longqing Zhang1 , Danning Wang1 , Shaodi Guan1 , Pei Lu1 , Xiaolin Xu1 , Hui Xu1

doi : 10.18632/aging.203746

Volume 13, Issue 23, pp: 25588—25601

Depression is the most common mental disorder and has become a heavy burden in modern society. Clinical studies have identified early life stress as one of the high-risk factors for increased susceptibility to depression. Alteration of the hypothalamic-pituitary-adrenal (HPA) axis in response to stress is one of the key risk factors for depression susceptibility related to early life stress. Laboratory animal studies have demonstrated that maternal separation (MS) for extended periods elicits HPA axis changes. These changes persist into adulthood and resemble those present in depressed adult individuals, including hyperactivity of the HPA axis. In addition, there is growing evidence that inflammation plays an important role in depression susceptibility concerned with early life stress. Individuals that have experienced MS have higher levels of pro-inflammatory cytokines and are susceptible to depression. Recently, it has been found that the gut microbiota plays an important role in regulating behavior and is also associated with depression. The translocation of gut microbiota and the change of gut microbiota composition caused by early stress may be a reason. In this review, we discussed the mechanisms by which early life stress contributes to the development of depression in terms of these factors. These studies have facilitated a systematic understanding of the pathogenesis of depression related to early life stress and will provide new ideas for the prevention and treatment of depression.

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Correction for: LncRNA LOC146880 promotes esophageal squamous cell carcinoma progression via miR-328-5p/FSCN1/MAPK axis

Jianwei Tang1, * , Honglei Xu1, * , Qiang Liu1, * , Jianan Zheng1, * , Cheng Pan1 , Zhihua Li1 , Wei Wen1 , Jun Wang1 , Quan Zhu1 , Zhibo Wang1 , Liang Chen1

doi : 10.18632/aging.203705

Volume 13, Issue 23, pp: 25602—25603

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