One-year access to more than 500 world journals available in the system
-
http://medilib.ir
- Duration of Time : 365 Day
Price : 300$- Special Price : 100$
Higher DNA repair in mitochondria of long-lived species
Gustavo Barja
doi : 10.18632/aging.203595
Volume 13, Issue 18 pp 21808—21809
Does chronic jet lag increase risk of cancer?
Suliman Khan, Mengzhou Xue, V. Wee Yong
doi : 10.18632/aging.203596
Volume 13, Issue 18 pp 21810—21811
SERPINA3 in glioblastoma and Alzheimer’s disease
Emily S. Norton, Sandro Da Mesquita, Hugo Guerrero-Cazares
doi : 10.18632/aging.203603
Volume 13, Issue 18 pp 21812—21813
Development of infrastructure for a systemic multidisciplinary approach to study aging in retired sled dogs
Daria I. Fleyshman1 , Joseph J. Wakshlag2 , Heather J. Huson3 , John P. Loftus2 , Natasha J. Olby4 , Leonid Brodsky5 , Andrei V. Gudkov1,6 , Ekaterina L. Andrianova1
doi : 10.18632/aging.203600
Volume 13, Issue 18 pp 21814—21837
Canines represent a valuable model for mammalian aging studies as large animals with short lifespans, allowing longitudinal analyses within a reasonable time frame. Moreover, they develop a spectrum of aging-related diseases resembling that of humans, are exposed to similar environments, and have been reasonably well studied in terms of physiology and genetics. To overcome substantial variables that complicate studies of privately-owned household dogs, we have focused on a more uniform population composed of retired Alaskan sled dogs that shared similar lifestyles, including exposure to natural stresses, and are less prone to breed-specific biases than a pure breed population. To reduce variability even further, we have collected a population of 103 retired (8-11 years-old) sled dogs from multiple North American kennels in a specialized research facility named Vaika. Vaika dogs are maintained under standardized conditions with professional veterinary care and participate in a multidisciplinary program to assess the longitudinal dynamics of aging. The established Vaika infrastructure enables periodic gathering of quantitative data reflecting physical, physiological, immunological, neurological, and cognitive decline, as well as monitoring of aging-associated genetic and epigenetic alterations occurring in somatic cells. In addition, we assess the development of age-related diseases such as arthritis and cancer. In-depth data analysis, including artificial intelligence-based approaches, will build a comprehensive, integrated model of canine aging and potentially identify aging biomarkers that will allow use of this model for future testing of antiaging therapies.
SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3
Utkarsh Tripathi1 , Rayhane Nchioua2 , Larissa G. P. Langhi Prata1 , Yi Zhu1,3 , Erin O. Wissler Gerdes1 , Nino Giorgadze1 , Tamar Pirtskhalava1 , Erik Parker6 , Ailing Xue1 , Jair Machado Espindola-Netto1 , Steffen Stenger4 , Paul D. Robbins5 , Laura J. Niedernhofer5 , Stephanie L. Dickinson6 , David B. Allison6 , Frank Kirchhoff2 , Konstantin Maria Johannes Sparrer2 , Tamar Tchkonia1,3 , James L. Kirkland1,3,7
doi : 10.18632/aging.203560
Volume 13, Issue 18 pp 21838—21854
Senescent cells, which arise due to damage-associated signals, are apoptosis-resistant and can express a pro-inflammatory, tissue-destructive senescence-associated secretory phenotype (SASP). We recently reported that a component of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surface protein, S1, can amplify the SASP of senescent cultured human cells and that a related mouse ?-coronavirus, mouse hepatitis virus (MHV), increases SASP factors and senescent cell burden in infected mice. Here, we show that SARS-CoV-2 induces senescence in human non-senescent cells and exacerbates the SASP in human senescent cells through Toll-like receptor-3 (TLR-3). TLR-3, which senses viral RNA, was increased in human senescent compared to non-senescent cells. Notably, genetically or pharmacologically inhibiting TLR-3 prevented senescence induction and SASP amplification by SARS-CoV-2 or Spike pseudotyped virus. While an artificial TLR-3 agonist alone was not sufficient to induce senescence, it amplified the SASP in senescent human cells. Consistent with these findings, lung p16INK4a+ senescent cell burden was higher in patients who died from acute SARS-CoV-2 infection than other causes. Our results suggest that induction of cellular senescence and SASP amplification through TLR-3 contribute to SARS-CoV-2 morbidity, indicating that clinical trials of senolytics and/or SASP/TLR-3 inhibitors for alleviating acute and long-term SARS-CoV-2 sequelae are warranted.
Centenarians exposed to the Spanish flu in their early life better survived to COVID-19
Michel Poulain1,2 , Dany Chambre3 , Giovanni Mario Pes4
doi : 10.18632/aging.203577
Volume 13, Issue 18 pp 21855—21865
Although it is known that mortality due to COVID-19 increases progressively with age, the probability of dying from this serious infection among the oldest-old population is little known, and controversial data are found in literature.
Efficacy and safety of current medications for treating severe and non-severe COVID-19 patients: an updated network meta-analysis of randomized placebo-controlled trials
Qinglin Cheng1,2, * , Junfang Chen1, * , Qingjun Jia1, * , Zijian Fang1, * , Gang Zhao1
doi : 10.18632/aging.203522
Volume 13, Issue 18 pp 21866—21902
Many recent studies have investigated the role of drug interventions for coronavirus disease 2019 (COVID-19) infection. However, an important question has been raised about how to select the effective and secure medications for COVID-19 patients. The aim of this analysis was to assess the efficacy and safety of the various medications available for severe and non-severe COVID-19 patients based on randomized placebo-controlled trials (RPCTs).
Comparison of the clinical characteristics and mortalities of severe COVID-19 patients between pre- and post-menopause women and age-matched men
Danyong Liu1,2, * , Han-Lin Ding3, * , Yao Chen4 , De-Hong Chen5 , Changming Yang6 , Liu-Ming Yang7 , Jessica Aijia Liu8 , Liangqing Zhang1 , Zhong-Yuan Xia9 , Xi-He Zhang7 , Shaoqing Lei9 , Zhengyuan Xia1,2,10
doi : 10.18632/aging.203532
Volume 13, Issue 18 pp 21903—21913
The mortality rate of young female COVID-19 patients is reported to be lower than that of young males but no significant difference in mortality was found between female and male COVID-19 patients aged over 65 years, and the underlying mechanism is unknown. We retrospectively analyzed clinical characteristics and outcomes of severely ill pre- and post-menopausal COVID-19 patients and compared with age-matched males. Of the 459 patients included, 141 aged ?55, among whom 19 died (16 males vs. 3 females, p<0.005). While for patients >55 years (n=318), 115 died (47 females vs. 68 males, p=0.149). In patients ?55 years old, the levels of NLR, median LDH, median c-reactive protein and procalcitonin were significantly higher while the median lymphocyte count and LCR were lower in male than in female (all p<0.0001). In patients over 55, these biochemical parameters were far away from related normal/reference values in the vast majority of these patients in both genders which were in contrast to that seen in the young group. It is concluded that the mortality of severely ill pre-menopausal but not post-menopausal COVID-19 female patients is lower than age-matched male. Our findings support the notion that estrogen plays a beneficial role in combating COVID-19.
Metformin-induced chemosensitization to cisplatin depends on P53 status and is inhibited by Jarid1b overexpression in non-small cell lung cancer cells
Tharcisio Citrangulo Tortelli Jr1 , Rodrigo Esaki Tamura1,2 , Mara de Souza Junqueira1 , Janio da Silva Mororó1 , Silvina Odete Bustos1 , Renato Jose Mendonça Natalino1 , Shonagh Russell3 , Laurent Désaubry4 , Bryan Eric Strauss1 , Roger Chammas1
doi : 10.18632/aging.203528
Volume 13, Issue 18 pp 21914—21940
Metformin has been tested as an anti-cancer therapy with potential to improve conventional chemotherapy. However, in some cases, metformin fails to sensitize tumors to chemotherapy. Here we test if the presence of P53 could predict the activity of metformin as an adjuvant for cisplatin-based therapy in non-small cell lung cancer (NSCLC). A549, HCC 827 (TP53 WT), H1299, and H358 (TP53 null) cell lines were used in this study. A549 cells were pre-treated with a sub-lethal dose of cisplatin to induce chemoresistance. The effects of metformin were tested both in vitro and in vivo and related to the ability of cells to accumulate Jarid1b, a histone demethylase involved in cisplatin resistance in different cancers. Metformin sensitized A549 and HCC 827 cells (but not H1299 and H358 cells) to cisplatin in a P53-dependent manner, changing its subcellular localization to the mitochondria. Treatment with a sub-lethal dose of cisplatin increased Jarid1b expression, yet downregulated P53 levels, protecting A549Res cells from metformin-induced chemosensitization to cisplatin and favored a glycolytic phenotype. Treatment with FL3, a synthetic flavagline, sensitized A549Res cells to cisplatin. In conclusion, metformin could potentially be used as an adjuvant for cisplatin-based therapy in NSCLC cells if wild type P53 is present.
Synergic association of diabetes mellitus and chronic kidney disease with muscle loss and cachexia: results of a 16-year longitudinal follow-up of a community-based prospective cohort study
Changhyun Lee1,2, * , Hyun Jung Kim3,4, * , Tae Ik Chang2 , Ea Wha Kang2 , Young Su Joo5 , Hyung Woo Kim6 , Jung Tak Park6 , Tae-Hyun Yoo6 , Shin-Wook Kang6 , Seung Hyeok Han6
doi : 10.18632/aging.203539
Volume 13, Issue 18 pp 21941—21961
Muscle loss is a serious complication in patients with diabetes mellitus (DM) and chronic kidney disease (CKD). However, studies on a long-term change in muscle mass presence or absence of DM and CKD are scarce. We included 6247 middle-aged adults from the Korean Genome and Epidemiology Study (KoGES) between 2001 and 2016. Bioimpedance analysis (BIA) was performed biennially. Patients were classified into four groups according to the presence or absence of DM and CKD. The primary outcome was muscle depletion, which was defined as a decline in fat-free mass index (FFMI) below the 10th percentile of all subjects. The secondary outcomes included the occurrence of cachexia, all-cause mortality, and the slopes of changes in fat-free mass and weight. During 73,059 person-years of follow-up, muscle depletion and cachexia occurred in 460 (7.4%) and 210 (3.4%), respectively. In the multivariable cause-specific hazards model, the risk of muscle depletion was significantly higher in subjects with DM alone than in those without DM and CKD (HR, 1.37; 95% CI, 1.04–1.80) and was strongly pronounced in subjects with both conditions (HR, 3.38; 95% CI, 1.30–8.75). The secondary outcome analysis showed consistent results. The annual decline rates in FFMI, fat mass, and body mass index (BMI) were the steepest in subjects with DM and CKD among the four groups. DM and CKD are synergically associated with muscle loss over time. In addition, the mortality risk is higher in individuals with muscle loss.
Dulaglutide improves muscle function by attenuating inflammation through OPA-1-TLR-9 signaling in aged mice
Phyu Phyu Khin1,2, * , Yeonhee Hong1, * , MyeongHoon Yeon1 , Dae Ho Lee3,4 , Jong Han Lee5 , Hee-Sook Jun1,2
doi : 10.18632/aging.203546
Volume 13, Issue 18 pp 21962—21974
Dulaglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabetes. However, its effects on muscle wasting due to aging are poorly understood. In the current study, we investigated the therapeutic potential and underlying mechanism of dulaglutide in muscle wasting in aged mice. Dulaglutide improved muscle mass and strength in aged mice. Histological analysis revealed that the cross-sectional area of the tibialis anterior (TA) in the dulaglutide-treated group was thicker than that in the vehicle group. Moreover, dulaglutide increased the shift toward middle and large-sized fibers in both young and aged mice compared to the vehicle. Dulaglutide increased myofiber type I and type IIa in young (18.5% and 8.2%) and aged (1.8% and 19.7%) mice, respectively, compared to the vehicle group. Peroxisome proliferator-activated receptor-gamma coactivator-1? (PGC-1?), a master regulator of mitochondrial biogenesis, decreased but increased by dulaglutide in aged mice. The expression of atrophic factors such as myostatin, atrogin-1, and muscle RING-finger protein-1 was decreased in aged mice, whereas that of the myogenic factor, MyoD, was increased in both young and aged mice following dulaglutide treatment. In aged mice, optic atrophy-1 (OPA-1) protein was decreased, whereas Toll-like receptor-9 (TLR-9) and its targeting inflammatory cytokines (interleukin-6 [IL-6] and tumor necrosis factor-? [TNF-?]) were elevated in the TA and quadriceps (QD) muscles. In contrast, dulaglutide administration reversed this expression pattern, thereby significantly attenuating the expression of inflammatory cytokines in aged mice. These data suggest that dulaglutide may exert beneficial effects in the treatment of muscle wasting due to aging.
Thymus hirtus sp. algeriensis Boiss. and Reut. volatile oil enhances TRAIL/Apo2L induced apoptosis and inhibits colon carcinogenesis through upregulation of death receptor pathway
Fatma Guesmi1,2 , Sahdeo Prasad1,3 , Manel Ben Ali4 , Ismail A. Ismail4 , Ahmed Landoulsi2
doi : 10.18632/aging.203552
Volume 13, Issue 18 pp 21975—21990
The aim of the study is to determine the anticancer activity of Thymus algeriensis (TS) and its underlying mechanisms using in vitro and in animal models.
Identification of colorectal cancer associated biomarkers: an integrated analysis of miRNA expression
André Fonseca1 , Sara Ventura Ramalhete1,2 , André Mestre1,2 , Ricardo Pires das Neves3,4 , Ana Marreiros1,2 , Pedro Castelo-Branco1,2,5, * , Vânia Palma Roberto1,2,6, *
doi : 10.18632/aging.203556
Volume 13, Issue 18 pp 21991—22029
Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. This complex disease still holds severe problems concerning diagnosis due to the high invasiveness nature of colonoscopy and the low accuracy of the alternative diagnostic methods. Additionally, patient heterogeneity even within the same stage is not properly reflected in the current stratification system. This scenario highlights the need for new biomarkers to improve non-invasive screenings and clinical management of patients.
Cerebral small vessel disease, systemic vascular characteristics and potential therapeutic targets
Salim Elyas1,2 , Damilola Adingupu1 , Kunihiko Aizawa1 , Francesco Casanova1 , Kim Gooding1 , Jonathan Fulford1 , Dave Mawson1 , Phillip E. Gates1 , Angela C. Shore1 , David Strain1,2
doi : 10.18632/aging.203557
Volume 13, Issue 18 pp 22030—22039
Cerebral small vessel disease (SVD) is prevalent in the elderly population and is associated with increased risk of dementia, stroke and disability. Currently there are no clear targets or strategies for the treatment of cerebral SVD. We set out to identify modifiable vascular treatment targets.
A2E-induced inflammation and angiogenesis in RPE cells in vitro are modulated by PPAR-?, -?/?, -?, and RXR antagonists and by norbixin
Valérie Fontaine1 , Mylène Fournié1 , Elodie Monteiro1 , Thinhinane Boumedine1 , Christine Balducci2 , Louis Guibout2 , Mathilde Latil2 , José-Alain Sahel1,3,4 , Stanislas Veillet2 , Pierre J. Dilda2 , René Lafont2 , Serge Camelo2
doi : 10.18632/aging.203558
Volume 13, Issue 18 pp 22040—22058
N-retinylidene-N-retinylethanolamine (A2E) plays a central role in age-related macular degeneration (AMD) by inducing angiogenesis and inflammation. A2E effects are mediated at least partly via the retinoic acid receptor (RAR)-?. Here we show that A2E binds and transactivates also peroxisome proliferator-activated receptors (PPAR) and retinoid X receptors (RXR). 9’-cis-norbixin, a di-apocarotenoid is also a ligand of these nuclear receptors (NR). Norbixin inhibits PPAR and RXR transactivation induced by A2E. Moreover, norbixin reduces protein kinase B (AKT) phosphorylation, NF-?B and AP-1 transactivation and mRNA expression of the inflammatory interleukins (IL) -6 and -8 and of vascular endothelial growth factor (VEGF) enhanced by A2E. By contrast, norbixin increases matrix metalloproteinase 9 (MMP9) and C-C motif chemokine ligand 2 (CCL2) mRNA expression in response to A2E. Selective PPAR-?, -?/? and –? antagonists inhibit the expression of IL-6 and IL-8 while only the antagonist of PPAR-? inhibits the transactivation of NF-?B following A2E exposure. In addition, a cocktail of all three PPARs antagonists and also HX531, an antagonist of RXR reproduce norbixin effects on inflammation. Altogether, A2E’s deleterious biological effects could be inhibited through PPAR and RXR regulation. Moreover, the modulation of these NR by norbixin may open new avenues for the treatment of AMD.
Sex, rurality and socioeconomical status in Spanish centennial population (2017)
Pedro Fuentes1 , Sandra Amador1 , Ana Maria Lucas-Ochoa1 , Lorena Cuenca-Bermejo1 , Emiliano Fernández-Villalba1 , Valeria Raparelli2 , Colleen Norris3 , Alexandra Kautzky-Willer4 , Karolina Kublickiene5 , Louise Pilote6 , María Trinidad Herrero1 , the GOING-FWD Consortium
doi : 10.18632/aging.203563
Volume 13, Issue 18 pp 22059—22077
World's population is exponentially aging as people reaching 100 years old has increased. The number of areas with the highest centennial population rates (Blue Zones), are significantly higher. Are there any determinant factors that favor this situation in Spain? The goal of this study was to determine the possible influence of sex, rurality and socioeconomic factors (Gross Domestic Product (GDP)) on the prevalence of the centennial population of the Spanish society. The Spanish register of inhabitants was published in 2017 by the National Statistics Institute.
The relationship between plasma free fatty acids, cognitive function and structural integrity of the brain in middle-aged healthy humans
Markus Herrmann1 , Sebastian Simstich1 , Günter Fauler1 , Edith Hofer2,3 , Eva Fritz-Petrin1 , Wolfgang Herrmann4 , Reinhold Schmidt2
doi : 10.18632/aging.203573
Volume 13, Issue 18 pp 22078—22091
The cerebral composition of ?-3 and ?-6 polyunsaturated fatty acids (PUFAs) is believed to influence cognitive function and structural damage of the aging brain. However, existing data is inconsistent.
Adulthood systemic inflammation accelerates the trajectory of age-related cognitive decline
Jolie Barter1 , Ashok Kumar1 , Linda Bean1 , Marissa Ciesla1 , Thomas C. Foster1,2
doi : 10.18632/aging.203588
Volume 13, Issue 18 pp 22092—22108
In order to understand the long-term effects of systemic inflammation, it is important to distinguish inflammation-induced changes in baseline cognitive function from changes that interact with aging to influence the trajectory of cognitive decline. Lipopolysaccharide (LPS; 1 mg/kg) or vehicle was administered to young adult (6 months) male rats via intraperitoneal injections, once a week for 7 weeks. Longitudinal effects on cognitive decline were examined 6 and 12 months after the initial injections. Repeated LPS treatment, in adults, resulted in a long-term impairment in memory, examined in aged animals (age 18 months), but not in middle-age (age 12 months). At 12 months following injections, LPS treatment was associated with a decrease in N-methyl-D-aspartate receptor-mediated component of synaptic transmission and altered expression of genes linked to the synapse and to regulation of the response to inflammatory signals. The results of the current study suggest that the history of systemic inflammation is one component of environmental factors that contribute to the resilience or susceptibility to age-related brain changes and associated trajectory of cognitive decline.
LHX9, a p53-binding protein, inhibits the progression of glioma by suppressing glycolysis
Xiangying Luo1 , Jianwei Ge2 , Tao Chen3 , Jinfang Liu1 , Ziyuan Liu1 , Changlong Bi1 , Song Lan1
doi : 10.18632/aging.203436
Volume 13, Issue 18 pp 22109—22119
LHX9 methylation has been reported in many tumors, but its functions and related mechanisms in glioma are still unknown and need to be verified.
Metformin inhibits hepatocellular carcinoma development by inducing apoptosis and pyroptosis through regulating FOXO3
Zetian Shen1,2 , Han Zhou2 , Aomei Li2 , Tiancong Wu2 , Xiaoqin Ji2 , Lei Guo3 , Xixu Zhu2 , Dagan Zhang4 , Xia He1
doi : 10.18632/aging.203464
Volume 13, Issue 18 pp 22120—22133
This study aimed to expand our understanding of metformin (Met) in inhibiting hepatocellular carcinoma (HCC) progression and to investigate its underlying mechanism. Met was administrated to HCC cells at 5, 10, and 20 ?M, after which the cell phenotype was evaluated. RNA-seq cluster analysis was used to screen for target genes modulated by Met. Luciferase activity and ChIP assays were performed to detect the effect of FOXO3 on the transcriptional activation of NLRP3. We evaluated the effect of Met and FOXO3 and on the growth of HCC cells in vivo. Met inhibited HCC cell proliferation and promoted apoptosis. Met also induced pyroptosis of HCC cells. FOXO3 was significantly upregulated by Met treatment, and FOXO3 activated transcription of NLRP3. Cells after Met treatment together with FOXO3 knockdown have a stronger colony formation and migration ability but a lower apoptosis rate compared to the Met treatment alone group. In vivo, Met inhibited HCC tumor growth. The tumors in Met treatment and FOXO3 knockdown group grew faster than in Met treatment group. Thus, Met attenuates HCC cell development by inducing apoptosis and pyroptosis. This effect of metformin is partially dependent on FOXO3 which can activate the transcription of NLRP3.
Rutin inhibited the advanced glycation end products-stimulated inflammatory response and extra-cellular matrix degeneration via targeting TRAF-6 and BCL-2 proteins in mouse model of osteoarthritis
Xiang Chen1, * , Mingchuan Yu1, * , Wei Xu1 , Linfeng Zou1 , Jing Ye1 , Yu Liu1 , Yuhong Xiao1 , Jun Luo1
doi : 10.18632/aging.203470
Volume 13, Issue 18 pp 22134—22147
Osteoarthritis (OA) is degenerative joint disorder mainly characterized by long-term pain with limited activity of joints, the disease has no effective preventative therapy. Rutin (RUT) is a flavonoid compound, present naturally. The flavonoid shows range of biological activities such as anti-inflammatory and anti-cancer effect. We screened RUT for its activity against osteoarthritis with in vivo and in vitro models of osteoarthritis.
Low expression of KIF20A suppresses cell proliferation, promotes chemosensitivity and is associated with better prognosis in HCC
Chuanxing Wu1 , Xiaosheng Qi1 , Zhengjun Qiu1 , Guilong Deng1, & , Lin Zhong1
doi : 10.18632/aging.203494
Volume 13, Issue 18 pp 22148—22163
This study analysed the microarray datasets from Gene Expression Omnibus (GEO) database, and aimed to identify novel potential hub genes associated with the progression of HCC via bioinformatics analysis and experimental validation. The common differentially expressed genes (DEGs) from five GEO datasets were screened using GEO2R tool. The expression and survival analysis of hub genes in HCC were performed using Gene Expression Profiling Interactive Analysis, UALCAN and Kaplan-Meier plotter tools. In vitro functional assays were used to determine the caspase-3, -9, cell proliferation and chemo-sensitivity of HCC cells. A total of 177 common DEGs were identified between normal liver and HCC tissues among these datasets. Functional enrichment and PPI network analysis identified 22 hub genes from the common DEGs. The mRNA expression of 22 hub genes was all significantly up-regulated in HCC tissues compared to that in normal liver tissues. Further survival analysis showed that 10 hub genes predicted poor prognosis of patients with HCC. More importantly, the in vitro functional studies demonstrated that KIF20A knockdown suppressed the HCC cell proliferation and promoted the chemosensitivity of HCC cells to cisplatin and sorafenib. In conclusion, the present study identified a total of 177 common DEGs among 5 GEO microarray datasets and found that 10 hub genes could predict the poor prognosis of patients with HCC using the comprehensive bioinformatics analysis. Furthermore, KIF20A silence suppressed cell proliferation and enhanced chemosensitivity in HCC cells. Further studies may be required to determine the mechanistic role of these hub genes in HCC progression.
SLCO1B3 promotes colorectal cancer tumorigenesis and metastasis through STAT3
Lianghui Zhi1,4 , Lianmei Zhao2 , Xue Zhang3 , Wei Liu4 , Bo Gao3 , Feifei Wang3 , Xiaoran Wang3 , Guiying Wang1,3
doi : 10.18632/aging.203502
Volume 13, Issue 18 pp 22164—22175
Solute carrier organic anion transporter family member 1B3 (SLCO1B3) is a gene that encodes an organic anion-transporting polypeptide (OATP) 1B3, a membrane-bound multi-specific transporter in hepatocytes. SLCO1B3 was first reported in hepatocytes. Later, it was found that its expression is higher in colorectal cancer (CRC) than in the adjacent normal tissue. However, the role of SLCO1B3 in CRC is not well elucidated. In this study, the correlation between SLCO1B3 and the overall survival (OS) of CRC patients was evaluated using data from the GEO database. This study evaluated the relationship between SLCO1B3 and the clinicopathological characteristics and prognosis of CRC patients. The effects of SLCO1B3 knockdown, on human CRC cell proliferation, migration, and invasion in vitro and CRC tumorigenesis and metastasis in vivo were also examined. In addition, next-generation sequencing was used to identify SLCO1B3 mediators. The results confirmed the association between SLCO1B3 and poor OS of CRC patients, and SLCO1B3 was identified as the top hub gene associated with the OS. The study showed that high SLCO1B3 expression was associated with poor tumor differentiation, advanced disease stage, tumor invasion, lymph node metastasis, and poor OS. Next-generation sequencing revealed that SLCO1B3 knockdown affected the expression of several genes involved in cancer invasion, metastasis, and DNA repair. Moreover, the western blot analysis showed that SLCO1B3 knockdown downregulated p-STAT3, MMP-2, and MMP-9. In summary, we demonstrated that SLCO1B3 acts as a novel carcinogen in the CRC that drives the CRC tumorigenesis and metastasis. SLCO1B3 inhibitors, alone or in combination with current drugs, may have therapeutic benefits in CRC.
Key genes affecting the progression of nasopharyngeal carcinoma identified by RNA-sequencing and bioinformatic analysis
Yihong Wang1, * , Manyi Li1, * , Yan Guo1, * , Haiping Huang1 , Xuelin Dong1 , Yangguang Sun1 , Jisheng Liu1
doi : 10.18632/aging.203521
Volume 13, Issue 18 pp 22176—22187
The present work was conducted to screen the potential biomarkers affecting nasopharyngeal carcinoma (NPC) progression through RNA-sequencing (RNA-seq), bioinformatic analysis and functional experiments.
Cx32 inhibits the autophagic effect of Nur77 in SH-SY5Y cells and rat brain with ischemic stroke
Fengfeng Ping3, *,# , Chao Zhang3, *,# , Xue Wang4 , Yan Wang2 , Danli Zhou2 , Jing Hu2 , Yanhua Chen2 , Jingjing Ling2 , Jia Zhou1
doi : 10.18632/aging.203526
Volume 13, Issue 18 pp 22188—22207
The pathogenesis of cerebral ischemia-reperfusion (I/R) is complex. Cx32 expression has been reported to be up-regulated in ischemic lesions of aged human brain. Nevertheless, the function of Cx32 during cerebral I/R is poorly understood. Autophagy is of vital importance in the pathogenesis of cerebral I/R. In the current study, we found that oxygen-glucose deprivation/reoxygenation (OGD/R) or I/R insult significantly induced the up-regulation of Cx32 and activation of autophagy. Inhibition of Cx32 alleviated OGD/R or I/R injury, and further activated autophagy. In addition, Nur77 expression was found to be up-regulated after OGD/R or I/R. After inhibiting Cx32, the expression of Nur77 was further increased and Nur77 was translocated from nucleus to mitochondrial. Inhibition of Cx32 also activated mitophagy by promoting autophagosome formation and up-regulating the expression of mitochondrial autophagy marker molecules. Of note, in the siNur77-transfected cells, the number of dysfunctional mitochondrial was increased, and mitophagy was suppressed, which aggravated OGD/R-induced neuronal injury. In conclusion, Cx32 might act as a regulatory factor of Nur77 controlling neuronal autophagy in the brains. Understanding the mechanism of this regulatory pathway will provide new insight into the role Cx32 and Nur77 in cerebral ischemia, offering new opportunities for therapeutics.
Involvement of c-Myc in low dose radiation-induced senescence enhanced migration and invasion of unirradiated cancer cells
Jyh-Der Leu1,6, * , Chung-Yih Wang2, * , Chia-Chien Lo3, * , Min-Ying Lin3 , Chun-Yuan Chang3,5 , Wen-Chin Hung1 , Shi-Ting Lin3 , Bo-Shen Wang3 , Yi-Jang Lee1,4
doi : 10.18632/aging.203527
Volume 13, Issue 18 pp 22208—22231
Ionizing radiation is known to cause cell apoptosis at high dose range, but little is known about the cellular response to low dose radiation. In this study, we found that conditioned medium harvested from WI-38 lung fibroblasts and H1299 lung adenocarcinoma cells exposed to 0.1Gy to 1Gy could enhance the migration and invasion of unirradiated H1299 cells in both 2D and 3D culturing circumstances. Low dose radiation did not induce apoptosis, but induced senescence in irradiated cells. We next examined the expression of immediately early genes including c-Myc and K-Ras. Although both genes could be up-regulated by low dose radiation, induction of c-Myc was more specific to low dose range (0.5Gy) at transcriptional and translational levels. Knockdown of c-Myc by shRNA could repress the senescence induced by low dose radiation. The conditioned medium of irradiated cells induced migration of unirradiated cells was also repressed by knockdown of c-Myc. The c-Myc inhibitor 10058-F4 could suppress low dose radiation induced cell senescence, and the conditioned medium harvested from irradiated cells pretreated with 10058-F4 also lost the ability to enhance the migration of unirradiated cells. The cytokine array analysis revealed that immunosuppressive monocyte chemoattractant protein-1 increased by low dose radiation could be repressed by 10058-F4. We also showed that 10058-F4 could suppress low dose radiation induced tumor progression in a xenograft tumor model. Taken together, current data suggest that -Myc is involved in low dose radiation induced cell senescence and potent bystander effect to increase the motility of unirradiated cells.
High prevalence of thyroid carcinoma in patients with insulin resistance: a meta-analysis of case-control studies
Junyu Zhao1,2, * , Qianping Zhang3, * , Yupeng Yang4 , Jinming Yao1,2 , Lin Liao1,2 , Jianjun Dong5
doi : 10.18632/aging.203529
Volume 13, Issue 18 pp 22232—22241
The association between insulin resistance and thyroid carcinoma is controversial. We conducted this meta-analysis of association between insulin resistance and thyroid carcinoma. There were 14 studies included in this meta-analysis. Random-effect model was used to merge the weighted mean difference value of fasting serum insulin level and the pooled effect shows that the level of fasting serum insulin is higher in patients with thyroid carcinoma than those of controls (1.88, 95% CI 0.87 to 2.90, P=0.0003). Random-effect model was used to estimate the pooled weighted mean difference and it shows that thyroid carcinoma patients have a higher level of homeostasis model assessment of insulin resistance (HOMA-IR) than patients without thyroid carcinoma (0.54, 95% CI 0.29 to 0.78, P<0.0001). Fixed-effect model with the odds ratio of insulin resistance shows that insulin resistance could increase the risk of thyroid carcinoma 216% compared with participants without insulin resistance (3.16, 95% CI 2.09 to 4.77, P<0.0001). In conclusion, insulin resistance might be a risk factor for thyroid carcinoma.
miR-21 regulates ischemic neuronal injury via the p53/Bcl-2/Bax signaling pathway
Honglin Yan1 , Wenxian Huang1 , Jie Rao1 , Jingping Yuan1
doi : 10.18632/aging.203530
Volume 13, Issue 18 pp 22242—22255
Focal cerebral ischemia leads to a large number of neuronal apoptosis, and secondary neuronal death is the main cause of cerebral infarction. MicroRNA-21 (miR-21) has been shown to be a strong anti-apoptosis and pro-survival factor in ischemia. However, the precise mechanism of miR-21 in ischemic neuroprotection remains largely unknown. In this study, miR-21 was down-regulated while p53 was up-regulated following ischemia in vitro and in vivo. Overexpression of miR-21 in vitro and in vivo substantially inhibited the expression of p53 following ischemia, while inhibition of miR-21 in vitro and in vivo promoted p53 expression following ischemia. Moreover, the miR-21/p53 axis regulated the expression of Bcl-2/Bax and abolished OGD/R-induced neuronal injury in vitro. Furthermore, overexpression of miR-21 in vivo reduced neuronal death, protected against ischemic damage, and improved neurological functions by inhibiting p53/Bcl-2/Bax signaling, while inhibition of miR-21 enhanced the p53/Bcl-2/Bax signaling and aggravated the ischemic neuronal injury in vivo. Our data uncover a novel mechanism of miR-21 in regulating cerebral ischemic neuronal injury by inhibiting p53/Bcl-2/Bax signaling pathway, which suggests that miR-21/p53 may be attractive therapeutic molecules for treatment of ischemic stroke.
Nucleotide variants in hepatitis B virus preS region predict the recurrence of hepatocellular carcinoma
Xi Chen1, * , Minfeng Zhang2, * , Nan Li2 , Rui Pu1 , Ting Wu1 , Yibo Ding1 , Peng Cai1 , Hongwei Zhang1 , Jun Zhao2 , Jianhua Yin1, & , Guangwen Cao1
doi : 10.18632/aging.203531
Volume 13, Issue 18 pp 22256—22275
Hepatitis B virus (HBV) variants in the preS region have been associated with hepatocellular carcinoma (HCC). However, the effect of the preS variants on HCC prognosis remains largely unknown. We aimed to identify the preS variants that reliably predict postoperative prognosis in HCC.
Improvement of cardiac function by mesenchymal stem cells derived extracellular vesicles through targeting miR-497/Smad7 axis
Min Chen2, * , Jianfei Chen2, * , Caiting Li1 , Ranjie Yu1 , Weiwen Chen3 , Cunrong Chen1, *
doi : 10.18632/aging.203533
Volume 13, Issue 18 pp 22276—22285
The extracellular vesicles (EVs) secreted by bone marrow mesenchymal stromal cells (MSCs) have the ability to improve Myocardial infarction (MI). Some microRNAs (miRNAs) including miR-497 and related target genes have been proved to be closely linked with heart diseases. However, EVs could regulate MI process through miR-497, and the mechanisms have not been fully reported.
ASXL1 promotes adrenocortical carcinoma and is associated with chemoresistance to EDP regimen
Liang Wang1, * , Yinfeng Lyu2, * , Yuqing Li2 , Kunping Li2 , Hui Wen2 , Chenchen Feng2 , Ning Li3
doi : 10.18632/aging.203534
Volume 13, Issue 18 pp 22286—22297
Adrenocortical carcinoma (ACC) is a rare but aggressive disease that lacks definitive treatment. We aim to evaluate role of ASXL1 in ACC and exploit its therapeutic merits therein. We performed in silico reproduction of datasets of the Cancer Genome Atlas (TCGA), GDSC (Genomics of Drug Sensitivity in Cancer) and Human Protein Atlas using platforms of cBioPortal, UALCAN, NET-GE, GSEA and GEPIA. Validation in ACC was performed in tissue, in vitro and in vivo using the NCI-H295R and SW-13 cells. ASXL1 was gained in over 50% of ACC cases with its mRNA overexpressed in DNA gained cases. ASXL1 overexpression was associated with recurrence and worsened prognosis in ACC. ASXL1 gain was associated with resistance to etoposide, doxorubicin and cisplatin (EDP). ASXL1 expression was positively correlated with FSCN1 expression. Targeting ASXL1 significantly impaired fitness of ACC cells, which could be in part rescued by FSCN1 overexpression. Targeting FSCN1 however could not rescue resistance to EDP induced by ASXL1 overexpression. Targeting ASXL1 sensitized ACC cells to EDP regimen but constitutive ASXL3 overexpression in SW-13 cells could induce resistance upon prolonged treatment. Functional gain of ASXL1 was common in ACC and exerted pro-tumorigenic and chemoresistance role. Targeting ASXL1 hold promise to ACC treatment.
AKR1B10 inhibits the proliferation and migration of gastric cancer via regulating epithelial-mesenchymal transition
Xinyu Shao1, * , Jue Wu2, * , Shunying Yu1 , Yuqing Zhou1 , Chunli Zhou1
doi : 10.18632/aging.203538
Volume 13, Issue 18 pp 22298—22314
Gastric cancer (GC) is a common malignancy around the world with a poor prognosis. Aldo-keto reductase family 1 member B10 (AKR1B10) is indispensable to cancer development and progression, which has served as a diagnostic biomarker for tumors. In our study, we demonstrated that the expression of AKR1B10 in GC tissues was significantly lower compared with normal gastric tissues. Subgroup analysis showed that, according to the clinic-pathological factors, the effect of the AKR1B10 expression level on the prognosis of GC patients was significantly different. Moreover, reduced expression of AKR1B10 promoted the ability of GC cells in proliferation and migration. Furthermore, increased AKR1B10 levels resulted in the opposite trend in vitro. Moreover, AKR1B10 was correlated with epithelial-mesenchymal transition (EMT) in a significant way. In vivo experiment, knockdown of AKR1B10 promoted the growth of tumor, increased Vimentin, and E-cadherin significantly. In summary, AKR1B10 is considered as a tumor suppressor in GC and is a promising therapeutic target.
High CTSL2 expression predicts poor prognosis in patients with lung adenocarcinoma
Junnian Song1, * , Jindong Jiang2, * , Na Wei1 , Zongsheng Duan3 , Gang Wang4 , Weiyun Pan5
doi : 10.18632/aging.203540
Volume 13, Issue 18 pp 22315—22331
Cathepsin like 2 (CTSL2) is a lysosomal cysteine protease, and may be associated with tumor metastasis. However, CTSL2 has not been reported as a biomarker in lung adenocarcinoma (LUAD). In this study, bioinformatics analysis using data from The Cancer Genome Atlas was performed. Wilcoxon rank-sum test and chi-square test were carried out. Kaplan-Meier and Cox regression were performed to evaluate the effect of CTSL2 expression in the overall survival. Our results indicated that CTSL2 in tumor was significantly higher than that in normal tissue (P < 0.001). High CTSL2 expression was significantly associated with age (P = 0.02), vital status (P < 0.001), and T classification (P = 0.03), and correlated with poor overall survival (HR = 1.62, 95% CI = 1.21–2.18, P = 0.001). CTSL2 expression was an independent risk factor for overall survival in patients with LUAD (HR = 1.52, 95% CI = 1.12–2.05, P = 0.006). A nomogram was plotted for illustration of CTSL2 expression on the risk of LUAD. Furthermore, in vitro cell experiments showed the CTSL2 promoted the proliferation and migration of A549 cells. In summary, high CTSL2 expression predicts poor prognosis in patients with LUAD.
METTL3-mediated m6A modification of KIF3C-mRNA promotes prostate cancer progression and is negatively regulated by miR-320d
Honggui Ma1 , Facai Zhang2 , Quliang Zhong2 , Jianquan Hou1
doi : 10.18632/aging.203541
Volume 13, Issue 18 pp 22332—22344
The occurrence of distant metastasis is one of the leading causes of death in patients with prostate cancer (PCa). It is confirmed that kinesin protein is associated with a variety of malignancies, and the KIF3 family is related to cancer, but the relationship between KIF3C and prostate cancer is not clear. Our experiments have confirmed that KIF3C is highly expressed in prostate cancer tissues and cell lines. Further, functional tests have proven that KIF3C can promote the growth migration and invasion of PCa. We used Starbase 3.0 to discover that methyltransferase like 3 (METTL3) interacts with KIF3C. Our hypothesis and experiments concluded that METTL3 induced m6A modification on KIF3C, promoting the stabilization of KIF3C-mRNA by IGF2 binding protein 1 (IGF2BP1). The prediction that miR-320d inhibits KIF3C expression by targeting METTL3 using the miRmap website, was later confirmed experimentally. Further, a recovery experiment was used to confirm that miR-320d inhibited the progression of prostate cancer. KIF3C was overexpressed in prostate cancer, promoting its growth migration and invasion was induced by miR-320d/METTL3 in an m6A dependent process.
Identifying critical genes associated with aneurysmal subarachnoid hemorrhage by weighted gene co-expression network analysis
Zhizhong Yan1,2,3, * , Qi Wu2, * , Wei Cai4 , Haitao Xiang5 , Lili Wen2 , An Zhang2 , Yaonan Peng2 , Xin Zhang2, & , Handong Wang1,2, &
doi : 10.18632/aging.203542
Volume 13, Issue 18 pp 22345—22360
Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening medical condition with a high mortality and disability rate. aSAH has an unclear pathogenesis, and limited treatment options are available. Here, we aimed to identify critical genes involved in aSAH pathogenesis using peripheral blood gene expression data of 43 patients with aSAH due to ruptured intracranial aneurysms and 18 controls with headache, downloaded from Gene Expression Omnibus. These data were used to construct a co-expression network using weighted gene co-expression network analysis (WGCNA). The biological functions of the hub genes were explored, and critical genes were selected by combining with differentially expressed genes analysis. Fourteen modules were identified by WGCNA. Among those modules, red, blue, brown and cyan modules were closely associated with aSAH. Moreover, 364 hub genes in the significant modules were found to play important roles in aSAH. Biological function analysis suggested that protein biosynthesis-related processes and inflammatory responses-related processes were involved in the pathology of aSAH pathology. Combined with differentially expressed genes analysis and validation in 35 clinical samples, seven gene (CD27, ANXA3, ACSL1, PGLYRP1, ALPL, ARG1, and TPST1) were identified as potential biomarkers for aSAH, and three genes (ANXA3, ALPL, and ARG1) were changed with disease development, that may provide new insights into potential molecular mechanisms for aSAH.
Identification of clinical trait-related small RNA biomarkers with weighted gene co-expression network analysis for personalized medicine in endocervical adenocarcinoma
Zhiwen Shi1,2, * , Xinyu Qu1,2, * , Chenyan Guo1,2, * , Lihong Zhang1 , Chuyue Peng3 , Zhu Xie3 , Keqin Hua1,2 , Junjun Qiu1,2, &
doi : 10.18632/aging.203543
Volume 13, Issue 18 pp 22361—22374
Endocervical adenocarcinoma (EAC) is an aggressive type of endocervical cancer. At present, molecular research on EAC mainly focuses on the genome and mRNA transcriptome, the investigation of small RNAs in EAC has not been fully described. Here, we systematically explored small RNAs in 14 EAC patients with different subtypes using small RNA sequencing. MiRNAs and tRNA-derived RNAs (tDRs) accounted for the majority of mapped reads and the total number of miRNAs and tDRs maintained a relative balance. To explore the correlations between small RNAs expression and EAC with different clinical characteristics, we performed the weighted gene co-expression network analysis (WGCNA) and screened for hub small RNAs. From the key modules, we identified 9 small RNAs that were significantly related to clinical characteristics in EAC patients. Gene ontology and pathway analyses revealed that these molecules were involved in the pathogenesis of EAC. Our work provided new insights into EAC pathogenesis and successfully identified several small RNAs as candidate biomarkers for diagnosis and prognosis of EAC.
A new mechanism of POCD caused by sevoflurane in mice: cognitive impairment induced by cross-dysfunction of iron and glucose metabolism
Xing Ge1, * , Yong Zuo1, * , Jinhong Xie1 , Xincheng Li1 , Yan Li1 , Anand Thirupathi2 , Peng Yu1 , Guofen Gao1 , Changhao Zhou3, & , Yanzhong Chang1 , Zhenhua Shi1
doi : 10.18632/aging.203544
Volume 13, Issue 18 pp 22375—22389
Sevoflurane (Sev) is a commonly used anesthetic in hospitals that can cause neurotoxicity. Postoperative cognitive dysfunction (POCD) is a common clinical problem induced by some anesthetics. However, the exact mechanism of neurotoxicity induced by Sev is unclear. Here we studied a new mechanism of POCD induced by Sev. We treated 15-month-old mice with 2% Sev for 6 hours, and we had found that Sev causes POCD. Using isobaric tags for relative and absolute quantitation (iTRAQ), we found that the transporter and the metabolism of carbohydrates and inorganic ions were involved in the cognitive impairment induced by Sev. Using synchrotron radiation micro-X-ray fluorescence (?-XRF), we showed that Sev caused the iron overload in the brain of 15-month-old mice. Subsequently, excessive iron led to oxidative stress and impaired mitochondrial function that further led to glucose metabolism disorder and reduced ATP production by regulating the expression of key enzyme genes or proteins including G6Pase, Pck1, and Cs. Meanwhile, Sev also inhibited the oxygen consumption rate and glucose absorption by downregulating the expression of glucose transporter 1 in cerebral vascular endothelial cells. The cross-dysfunction of iron and glucose metabolism caused the apoptosis in the cortex and hippocampus through Bcl2/Bax pathway. In conclusion, the data here showed a new mechanism that Sev caused apoptosis by cross-dysregulation of iron and glucose metabolism and induced energy stress in mice. Maintaining iron and glucose metabolism homeostasis may play an important role in cognitive impairment induced by Sev.
Deficiency of miR-29b2/c leads to accelerated aging and neuroprotection in MPTP-induced Parkinson’s disease mice
Xiaochen Bai1,2, * , Xiaoshuang Zhang1, * , Rong Fang1, * , Jinghui Wang1, * , Yuanyuan Ma1 , Zhaolin Liu1 , Hongtian Dong1 , Qing Li1 , Jingyu Ge1 , Mei Yu1 , Jian Fei3,4 , Ruilin Sun4 , Fang Huang1
doi : 10.18632/aging.203545
Volume 13, Issue 18 pp 22390—22411
Studies reveal a linkage of miR-29s in aging and Parkinson’s disease (PD). Here we show that the serum levels of miR-29s in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice exhibited dynamic changes. The role of miR-29b2/c in aging and PD was studied utilizing miR-29b2/c gene knockout mice (miR-29b2/c KO). miR-29b2/c KO mice were characterized by a markedly lighter weight, kyphosis, muscle weakness and abnormal gait, when compared with wild-type (WT) mice. The WT also developed apparent dermis thickening and adipose tissue reduction. However, deficiency of miR-29b2/c alleviated MPTP-induced damages of the dopaminergic system and glial activation in the nigrostriatal pathway and consequently improved the motor function of MPTP-treated KO mice. Knockout of miR-29b2/c inhibited the expression of inflammatory factors in 1-methyl-4-phenylpyridinium (MPP+)-treated primary cultures of mixed glia, primary astrocytes, or LPS-treated primary microglia. Moreover, miR-29b2/c deficiency enhanced the activity of AMPK but repressed the NF-?B p65 signaling in glial cells. Our results show that miR-29b2/c KO mice display the progeria-like phenotype. Less activated glial cells and repressed neuroinflammation might bring forth dopaminergic neuroprotection in miR-29b2/c KO mice. Conclusively, miR-29b2/c is involved in the regulation of aging and plays a detrimental role in Parkinson’s disease.
Pim-2 kinase inhibits inflammation by suppressing the mTORC1 pathway in atherosclerosis
Minqi Liao1, * , Feng Hu2, * , Zhiqiang Qiu3 , Juan Li4 , Chahua Huang2 , Yan Xu2 , Xiaoshu Cheng2
doi : 10.18632/aging.203547
Volume 13, Issue 18 pp 22412—22431
Inflammatory immunity theory has raised considerable concern in the pathogenesis of atherosclerosis. Proviral integration site of murine 2 (Pim-2) kinases functions in apoptosis pathways and the anti-inflammatory response. Here, we investigated whether Pim-2 kinase inhibits atherosclerotic inflammation by suppressing the mTORC1 pathway.
Circular RNA Foxo3 enhances progression of ovarian carcinoma cells
Li Wang1 , Jing Chen1 , Chunhua Lu2
doi : 10.18632/aging.203550
Volume 13, Issue 18 pp 22432—22443
Ovarian carcinoma (OC) is the deadliest gynecologic malignancy in females worldwide. Circular RNA Foxo3 (Foxo3) plays essential roles in various cancers. However, the detailed function of Foxo3 in OC remains unclear. This study aimed to investigate the role of Foxo3 in OC and the underlying molecular mechanism.
SUV39H2/KMT1B Inhibits the cardiomyocyte senescence phenotype by down-regulating BTG2/PC3
Kan Wang1,2 , Qiang Zhang Zhu1 , Xian Tao Ma1 , Cai Cheng1
doi : 10.18632/aging.203551
Volume 13, Issue 18 pp 22444—22458
Suppressor of variegation 3-9 homolog 2 (SUV39H2/KMT1B), a member of the SUV39 subfamily of lysine methyltransferases (KMTs), functions as an oncogene in various types of cancers. Here, we demonstrate a novel function of SUV39H2 that drives the cardiomyocyte aging process through BTG2. In our study, cardiomyocyte aging was induced by H2O2 and aging cells exhibited increases in SUV39H2. Knockdown of SUV39H2 accelerated cardiomyocyte senescence, while overexpression of SUV39H2 inhibited the cardiomyocyte senescence phenotype. These effects of SUV39H2 on cardiomyocytes were independent of DNA damage and mitochondrial dysfunction. Interestingly, RNA sequencing and bioinformatics analyses identified a strong correlation between SUV39H2 and BTG2. In addition to this, BTG2 protein levels were significantly increased in SUV39H2-deficient cardiomyocytes, and BTG2 knockdown virtually rescued the cardiomyocyte senescence phenotype induced by SUV39H2 knockdown. Taken together, these results indicate that SUV39H2 protects cardiomyocytes from H2O2 exposure-induced oxidative stress, DNA damage, and mitochondrial dysfunction by regulating the p53-BTG2 pathway. Our findings provide evidence that the activation of SUV39H2 has therapeutic or preventive potential against cardiac aging.
miR-19b-3p relieves intervertebral disc degeneration through modulating PTEN/PI3K/Akt/mTOR signaling pathway
Yulin Zhao1 , Aimin Li1
doi : 10.18632/aging.203553
Volume 13, Issue 18 pp 22459—22473
Emerging studies have revealed that non-coding RNAs contribute to regulating intervertebral disc degeneration (IVDD). Here, we intended to probe into the function of miR-19b-3p in IVDD evolvement. The miR-19b-3p level in the intervertebral disc (IVD) tissues of IVDD patients and IL-1?/TNF-?/hydrogen peroxide-treated human nucleus pulposus cells (HNPCs) was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Also, qRT-PCR was conducted to examine the profiles of MMP-3, MMP-9, MMP-13, ADAMTS-4 and ADAMTS-5. The PTEN/PI3K/Akt/mTOR pathway was examined by Western blot (WB). The miR-19b-3p overexpression assay was carried out, and HNPC proliferation and apoptosis were compared by the cell counting kit-8 (CCK-8) assay and flow cytometry (FCM). In addition, the mechanism of action of miR-19b-3p was clarified using the PTEN inhibitor (VO-Ohpic triphosphate) or the mTOR inhibitor (Rapamycin) on the basis of IL-1? intervention and miR-19b-3p mimics transfection. Our results testified that miR-19b-3p expression was curbed in IVD tissues of the IVDD patients (vs. normal IVD tissues) and IL-1?-, TNF-?, or hydrogen peroxide-treated HNPCs. Up-regulating miR-19b-3p enhanced HNPC proliferation and hampered its apoptosis. Moreover, miR-19b-3p dampened the PTEN profile and activated the PI3K/Akt/mTOR pathway. Interestingly, attenuating PTEN reduced IL-1?-, TNF-?-, or hydrogen peroxide-mediated HNPC apoptosis and up-regulated PI3K/Akt/mTOR, while inhibiting the mTOR pathway offset the protective function of miR-19b-3p. Further mechanism studies illustrated that miR-19b-3p targeted the 3’untranslated region (UTR) of PTEN and abated the PTEN level. This research confirmed that miR-19b-3p suppressed HNPC apoptosis in the in-vitro model of IVDD by regulating PTEN/PI3K/Akt/mTOR pathway.
Identification of genes and pathways leading to metastasis and poor prognosis in melanoma
Xin Zhang1,2 , Wandong Wang1,2 , Yun Wang1,2 , Guan Jiang1,2
doi : 10.18632/aging.203554
Volume 13, Issue 18 pp 22474—22489
Melanoma causes the highest mortality rate among all skin cancers. However, the underlying molecular mechanisms leading to metastasis and poor prognosis in melanoma have not been fully elucidated. In this study, the differentially expressed genes (DEGs) related to metastasis in melanoma were screened out. The results of gene annotation was combined with The Cancer Genome Atlas (TCGA) database. The microRNA (miRNA) network that regulates key genes and their correlation with BRAFV600E was preliminarily analyzed. Cell and molecular biology experiments were conducted to verify the results of bioinformatics analysis. Results showed that the PI3K-Akt signaling pathway contained the key genes CDK2, CDK4, KIT, and Von Willebrand factor. Survival analysis showed that high expression of the four key genes significantly reduced the survival rate of patients with melanoma. Correlation analysis showed that BRAFV600E may regulate the expression of the four key genes, and a total of 240 miRNAs may regulate this expression. Experiments showed that the inactivation of key genes inhibits the proliferation, migration, and invasion of melanoma. In conclusion, the PI3K-Akt signaling pathway and the four key genes promoted the proliferation, migration, and invasion of melanoma, and related to poor prognosis of patients with melanoma.
Nesfatin-1 facilitates IL-1? production in osteoarthritis synovial fibroblasts by suppressing miR-204-5p synthesis through the AP-1 and NF-?B pathways
Kun-Tsan Lee1,2 , Bo-Cheng Chen3 , Shan-Chi Liu4 , Yen-You Lin3 , Chun-Hao Tsai5,6 , Chih-Yuan Ko6 , Chih-Hsin Tang3,7,8 , Kwong-Chung Tung1
doi : 10.18632/aging.203559
Volume 13, Issue 18 pp 22490—22501
The progression of osteoarthritis (OA) is mediated by adipokines, one of which is nesfatin-1, which is responsible for the production of inflammatory cytokines. However, how this molecule may affect the synthesis of the proinflammatory cytokine interleukin 1 beta (IL-1?) in OA is unclear. Our analyses of records from the Gene Expression Omnibus (GEO) dataset and clinical specimens of synovial tissue revealed higher levels of nesfatin-1 and IL-1? in OA samples compared with normal healthy tissue. We found that nesfatin-1 facilitates IL-1? synthesis in human OA synovial fibroblasts (OASFs) and suppresses the generation of micro-RNA (miR)-204-5p, as the miR-204-5p levels in OA patients were lower than those in healthy controls. Nesfatin-1-induced stimulation of IL-1? in human OASFs occurred via the suppression of miR-204-5p synthesis by the PI3K, Akt, AP-1 and NF-?B pathways. We suggest that nesfatin-1 is worth targeting in OA treatment.
Melatonin inhibits proliferation, migration, and invasion by inducing ROS-mediated apoptosis via suppression of the PI3K/Akt/mTOR signaling pathway in gallbladder cancer cells
Kunlun Chen1, * , Pengfei Zhu1, * , Wenhui Chen1 , Kai Luo1 , Xiao-Jing Shi2 , Wenlong Zhai1
doi : 10.18632/aging.203561
Volume 13, Issue 18 pp 22502—22515
Melatonin is an indolic compound mainly secreted by the pineal gland and plays a vital role in the regulation of circadian rhythms and cancer therapy. However, the effects of melatonin in gallbladder cancer (GBC) and the related mechanism remain unknown.
miR-320 accelerates chronic heart failure with cardiac fibrosis through activation of the IL6/STAT3 axis
Fang Li1 , Shan-Shan Li1 , Hui Chen1 , Jian-Zhi Zhao2 , Jie Hao1 , Jin-Ming Liu1 , Xiu-Guang Zu1 , Wei Cui3
doi : 10.18632/aging.203562
Volume 13, Issue 18 pp 22516—22527
Cardiac fibrosis could induce abnormal cardiac function and become a novel target for cardiac hypertrophy and chronic heart failure. MiRNA-320 is a crucial miRNA in cardiovascular disease, but it is poorly understood whether it plays a role in cardiac fibrosis pathogenesis. We aimed to identify the specific underlying mechanism of miR-320 in cardiac fibrosis and hypertrophic pathogenesis. In our study, the GEO datasets revealed that STAT3 was significantly highly expressed in cardiomyocyte lines. MiR-320 activation and STAT3 signaling pathways were statistically significantly connected. Furthermore, miR-320 was highly associated with cardiac fibrosis and hypertrophic disease. Interstitial fibrosis was observed in the mice subjected to TAC surgery, markedly enhanced in miR-320 mimics. Mechanistically, we revealed that miR-320 mimics aggravated the pressure overload and induced cardiac hypertrophy and fibrosis via the IL6/STAT3/PTEN axis. MiR-320 mimics accelerated cardiac hypertrophy and cardiac fibrosis via the IL6/STAT3/PTEN axis. These results suggest that targeting miR-320 may represent a potential therapeutic strategy for cardiac hypertrophy and fibrosis.
Inhibition of FSTL3 abates the proliferation and metastasis of renal cell carcinoma via the GSK-3?/?-catenin signaling pathway
Fengfeng Sun1 , Peng Sun1 , Xiaofeng Yang1 , Liangliang Hu1 , Jianguo Gao1 , Tao Tian1
doi : 10.18632/aging.203564
Volume 13, Issue 18 pp 22528—22543
Renal cell carcinoma (RCC) is a lethal malignancy of the genitourinary system. Follistatin-like 3 (FSTL3), which mediates cell differentiation and growth, acts as a biomarker of tumors and participates in cancer development and progression. Presently, the FSTL3’s functions in RCC were investigated. Quantitative reverse transcription PCR (qRT-PCR), Western Blot, and enzyme linked immunosorbent assay (ELISA) were conducted to verify FSTL3 expression in RCC tissues and cell lines. BrdU assay and CCK8 experiment were made to monitor cell proliferation. Transwell was implemented to examine the invasion of the cells. Flow cytometry analyzed cell apoptosis, and Western Blot evaluated the protein levels of E-cadherin, Twist, and Slug. In the meantime, the protein profiles of the GSK-3?, ?-catenin, and TGF-? signaling pathways were ascertained. Moreover, the Xenograft tumor model was constructed in nude mice for measuring tumor growth in vivo. The statistics showed that FSTL3 presented an overexpression in RCC, and patients with a lower expression of FSTL3 manifested a better prognosis. Down-regulated FSTL3 hampered the proliferation, invasion, EMT, and tumor growth of RCC cells and caused cell apoptosis. On the contrary, FSTL3 overexpression enhanced the malignant behaviors of RCC cells. Furthermore, FSTL3 knockdown bolstered GSK-3?, suppressed ?-catenin, and reduced BMP1-SMAD pathway activation. Inhibited ?-catenin substantially mitigated FSTL3-mediated promoting functions in RCC. In short, FSTL3 functions as an oncogene in RCC by modulating the GSK-3?/?-catenin signaling pathway.
Glaucocalyxin B inhibits cartilage inflammatory injury in rheumatoid arthritis by regulating M1 polarization of synovial macrophages through NF-?B pathway
Chenyang Han1, * , Yi Yang1, * , Yongjia Sheng1 , Jin Wang1 , Xiaohong Zhou2 , Wenyan Li1 , Li Guo2 , Caiqun Zhang1 , Qiao Ye3
doi : 10.18632/aging.203567
Volume 13, Issue 18 pp 22544—22555
Glaucocalyxin B (Gla B) is a type of sesquiterpenoids. At present, there are rare studies on the pharmacological effects and targets of sesquiterpenoids, while multiple sesquiterpenoids have good anti-inflammatory properties. Therefore, in this study, we aimed to investigate the mechanism of Gla B on macrophages and rheumatoid arthritis.
MSCs enhances the protective effects of valsartan on attenuating the doxorubicin-induced myocardial injury via AngII/NOX/ROS/MAPK signaling pathway
Dong Cheng1,2 , Wencheng Tu2,3 , Libo Chen1,4 , Haoren Wang5 , Qinfu Wang6 , Hainiang Liu1,2 , Ning Zhu7 , Weiyi Fang8 , Qin Yu1
doi : 10.18632/aging.203569
Volume 13, Issue 18 pp 22556—22570
To verify if AngII/NOX/ROS/MAPK signaling pathway is involved in Doxorubicin (DOX)-induced myocardial injury and if mesenchymal stem cells (MSCs) could enhance the protective effects of valsartan (Val) on attenuating DOX-induced injury in vitro.
Helicobacter pylori infection and risk for developing dementia: an evidence-based meta-analysis of case-control and cohort studies
Nan-Yang Liu1, * , Jia-Hui Sun2, * , Xue-Fan Jiang2 , Hao Li1,3
doi : 10.18632/aging.203571
Volume 13, Issue 18 pp 22571—22587
Infection with multiple pathogens may play a key role in the pathogenesis of dementia. Whether Helicobacter pylori (H. pylori) infection is associated causally with dementia is controversial.
GPR43 regulation of mitochondrial damage to alleviate inflammatory reaction in sepsis
Weiwei Zhang1, * , Wusan Wang2, * , Maodi Xu3 , Haitang Xie3, & , Zhichen Pu3,4
doi : 10.18632/aging.203572
Volume 13, Issue 18 pp 22588—22610
Sepsis is a common critical illness in ICU and always a great difficulty in clinical treatment. GPR43 (G protein-coupled receptor 43) participates in regulating appetite and gastrointestinal peptide secretion to modulate fat decomposition and formation. However, the biological contribution of GPR43 on inflammation of sepsis has not been previously investigated. We investigated the mechanisms of GPR43 gene, which plays a possible role in distinguishing sepsis and contributes to the pathogenesis of sepsis-induced inflammatory reaction. Furthermore, we performed studies with mice induced to sepsis by Cecal Ligation and Puncture (CLP), Knockout GPR43 (GPR43-/-) mice, and Wild Type (WT) mice induced with CLP. In addition, lung tissues and cell samples were analyzed by histology, Quantitative Polymerase Chain Reaction (Q-PCR), Enzyme-linked Immunosorbent (ELISA) Assay, and western blot. GPR43 agonist could significantly reduce inflammation reactions and trigger lung injury in mice with sepsis. As for GPR43-/- mice, the risks of sepsis-induced inflammatory reactions and corresponding lung injury were promoted. On the one hand, the up-regulation of GPR43 gene reduced ROS mitochondrial damage to inhibit inflammatory reactions via the inactivation of NLRP3 Inflammasome by PPAR?/ Nox1/EBP50/ p47phox signal channel. On the other hand, the down-regulation of GPR43 promoted inflammatory reactions in vitro model through the acceleration of ROS-dependently mitochondrial damage by PPAR?/ Nox1/EBP50/ p47phox/ NLRP3 signal channel. These findings indicate that the inhibition of GPR43 as a possible important factor of sepsis may shed lights on the mechanism of sepsis-induced inflammation reaction.
Applying deductive reasoning and the principles of particle physics to aging research
Alibek Moldakozhayev1,2, * , Albina Tskhay3, * , Vadim N. Gladyshev4
doi : 10.18632/aging.203555
Volume 13, Issue 18 pp 22611—22622
Aging is debatably one of the biggest mysteries for humanity, a process consisting of myriads of genetic, molecular, environmental, and stochastic deleterious events, leading to a progressive loss of organism functionality. Aging research currently lacks a common conceptual framework, and one challenge in establishing it is the fact that aging is a highly complex process. To help develop a framework of standard aging rules, we suggest the use of deductive reasoning based on particle physics' principles. Specifically, the principles that we suggest applying to study aging are discreteness of processes, transformation as a result of interaction, and understanding of threshold. Using this framework, biological aging may be described as a sequence of highly discrete molecular transformations caused by a combination of various specific internal and external factors. Internal organismal function and interaction of an organism with the environment result in chronic accumulation of molecular damage and other deleterious consequences of metabolism and the consequent loss of system's functionality. The loss of functionality occurs as a series of thresholds the organism reaches before it turns into an utterly non-functional state. We discuss how having a common ground may benefit aging research, introduce the logic of new principles and analyze specific examples of how this framework could be used to study aging and design longevity interventions.
Correction for: The role of serum growth hormone and insulin-like growth factor-1 in adult humans brain morphology
Taoyang Yuan1 , Jianyou Ying1 , Lu Jin2 , Chuzhong Li1 , Songbai Gui2 , Zhenye Li2 , Rui Wang1 , Zhentao Zuo3,4,5 , Yazhuo Zhang1,2,6
doi : 10.18632/aging.203601
Volume 13, Issue 18 pp 22623—22624
