دسترسی یکساله به بیش از ۵۰۰ ژورنال روز جهان موجود در سامانه
-
http://medilib.ir
- ﻣﺪﺕ ﺯﻣﺎﻥ : 365 ﺭﻭﺯ
قیمت : 3,800,000 تومان- قیمت ویژه : 1,900,000تومان
GWAS of canines identifies potential aging determinants
Timothy M. Robinette, Sergiy Libert
doi : 10.18632/aging.203661
Volume 13, Issue 21, pp 23872—23873
Aging and brain connectivity by graph theory
Fabrizio Vecchio
doi : 10.18632/aging.203680
Volume 13, Issue 21, pp 23874—23875
Alteration of mitochondrial homeostasis is an early event in a C. elegans model of human tauopathy
Konstantinos Palikaras1,2, * , Kavya Achanta1, * , Seoyun Choi3 , Mansour Akbari1 , Vilhelm A. Bohr1,3
doi : 10.18632/aging.203683
Volume 13, Issue 21, pp 23876—23894
Tauopathies are a group of progressive neurodegenerative disorders characterized by the presence of insoluble intracellular tau filaments in the brain. Evidence suggests that there is a tight connection between mitochondrial dysfunction and tauopathies, including Alzheimer’s disease. However, whether mitochondrial dysfunction occurs prior to the detection of tau aggregates in tauopathies remains elusive. Here, we utilized transgenic nematodes expressing the full length of wild type tau in neuronal cells and monitored mitochondrial morphology alterations over time. Although tau-expressing nematodes did not accumulate detectable levels of tau aggregates during larval stages, they displayed increased mitochondrial damage and locomotion defects compared to the control worms. Chelating calcium restored mitochondrial activity and improved motility in the tau-expressing larvae suggesting a link between mitochondrial damage, calcium homeostasis and neuronal impairment in these animals. Our findings suggest that defective mitochondrial function is an early pathogenic event of tauopathies, taking place before tau aggregation and undermining neuronal homeostasis and organismal fitness. Understanding the molecular mechanisms causing mitochondrial dysfunction early in tauopathy will be of significant clinical and therapeutic value and merits further investigation.
Role of tumor necrosis factor-? in the mortality of hospitalized patients with severe and critical COVID-19 pneumonia
Fang Jia1 , Gang Wang2 , Jing Xu1 , Junhong Long1 , Fuxue Deng3, * , Wei Jiang3, *
doi : 10.18632/aging.203663
Volume 13, Issue 21, pp 23895—23912
The coronavirus disease 2019 (COVID-19) is presently the most pressing public health concern worldwide. Cytokine storm is an important factor leading to death of patients with COVID-19. This study aims to characterize serum cytokines of patients with severe or critical COVID-19. Clinical records were obtained from 149 patients who were tested at the Sino-French New City Branch of Tongji Hospital from 30 January to 30 March 2020. Data regarding the clinical features of the patients was collected and analyzed. Among the 149, 45 (30.2%) of them had severe conditions and 104 (69.8%) of that presented critical symptoms. In the meantime, 80 (53.7%) of that 149 died during hospitalization. Of all, male patients accounted for 94 (69.1%). Compared with patients in severe COVID-19, those who in critical COVID-19 had significantly higher levels of tumor necrosis factor-? (TNF-?), interleukin-6 (IL-6), IL-8, and IL-10. Moreover, the passed-away patients had considerably higher levels of TNF-?, IL-6, IL-8, and IL-10 than those survived from it. Regression analysis revealed that serum TNF-? level was an independent risk factor for the death of patient with severe conditions. Among the proinflammatory cytokines (IL-1?, TNF-?, IL-8, and IL-6) analyzed herein, TNF-? was seen as a risk factor for the death of patients with severe or critical COVID-19. This study suggests that anti-TNF-? treatment allows patients with severe or critical COVID-19 pneumonia to recover.
New tale on LianHuaQingWen: IL6R/IL6/IL6ST complex is a potential target for COVID-19 treatment
Zhao Tianyu1 , Cui Xiaoli1 , Wang Yaru1 , Zhang Min1 , Yue Fengli1 , He Kan1 , Chen Li1 , Li Jing1
doi : 10.18632/aging.203666
Volume 13, Issue 21, pp 23913—23935
LianHuaQingWen (LHQW) improves clinical symptoms and alleviates the severity of COVID-19, but the mechanism is unclear. This study aimed to investigate the potential molecular targets and mechanisms of LHQW in treating COVID-19 using a network pharmacology-based approach and molecular docking analysis. The main active ingredients, therapeutic targets of LHQW, and the pathogenic targets of COVID-19 were screened using the TCMSP, UniProt, STRING, and GeneCards databases. According to the “Drug-Ingredients-Targets-Disease” network, Interleukin 6 (IL6) was identified as the core target, and quercetin, luteolin, and wogonin as the active ingredients of LHQW associated with IL6. The response to lipopolysaccharide was the most significant biological process identified by gene ontology enrichment analysis, and AGE-RAGE signaling pathway activation was prominent based on the interaction between LHQW and COVID-19. Protein-protein docking analysis showed that IL6 receptor (IL6R)/IL6/IL6 receptor subunit beta (IL6ST) and Spike protein were mainly bound via conventional hydrogen bonds. Furthermore, protein-small molecule docking showed that all three active ingredients could bind stably in the binding model of IL6R/IL6 and IL6ST. Our findings suggest that LHQW may inhibit the lipopolysaccharide-mediated inflammatory response and regulate the AGE-RAGE signaling pathway through IL6. In addition, the N-terminal domain of the S protein of COVID-19 has a good binding activity to IL6ST, and quercetin and wogonin in LHQW may affect IL6ST-mediated IL6 signal transduction and a large number of signaling pathways downstream to other cytokines by directly affecting protein-protein interaction. These findings suggest the potential molecular mechanism by which LHQW inhibits COVID-19 through the regulation of IL6R/IL6/IL6ST.
Impaired glucose metabolism reduces the neuroprotective action of adipocytokines in cognitively normal older adults with insulin resistance
Karel M. Lopez-Vilaret1 , Jose L. Cantero1,2 , Marina Fernandez-Alvarez1,2 , Miguel Calero2,3 , Olga Calero2,3 , Mónica Lindín4 , Montserrat Zurrón4 , Fernando Díaz4 , Mercedes Atienza1,2
doi : 10.18632/aging.203668
Volume 13, Issue 21, pp 23936—23952
Evidence suggests that aging-related dysfunctions of adipose tissue and metabolic disturbances increase the risk of diabetes and metabolic syndrome (MtbS), eventually leading to cognitive impairment and dementia. However, the neuroprotective role of adipocytokines in this process has not been specifically investigated. The present study aims to identify metabolic alterations that may prevent adipocytokines from exerting their neuroprotective action in normal ageing. We hypothesize that neuroprotection may occur under insulin resistance (IR) conditions as long as there are no other metabolic alterations that indirectly impair the action of adipocytokines, such as hyperglycemia. This hypothesis was tested in 239 cognitively normal older adults (149 females) aged 52 to 87 years (67.4 ± 5.9 yr). We assessed whether the homeostasis model assessment-estimated insulin resistance (HOMA-IR) and the presence of different components of MtbS moderated the association of plasma adipocytokines (i.e., adiponectin, leptin and the adiponectin to leptin [Ad/L] ratio) with cognitive functioning and cortical thickness. The results showed that HOMA-IR, circulating triglyceride and glucose levels moderated the neuroprotective effect of adipocytokines. In particular, elevated triglyceride levels reduced the beneficial effect of Ad/L ratio on cognitive functioning in insulin-sensitive individuals; whereas under high IR conditions, it was elevated glucose levels that weakened the association of the Ad/L ratio with cognitive functioning and with cortical thickness of prefrontal regions. Taken together, these findings suggest that the neuroprotective action of adipocytokines is conditioned not only by whether cognitively normal older adults are insulin-sensitive or not, but also by the circulating levels of triglycerides and glucose, respectively.
UBB+1 reduces amyloid-? cytotoxicity by activation of autophagy in yeast
Xin Chen1,2, * , Ana Joyce Muñoz-Arellano1, * , Dina Petranovic1,2
doi : 10.18632/aging.203681
Volume 13, Issue 21, pp 23953—23980
UBB+1 is a mutated version of ubiquitin B peptide caused by a transcriptional frameshift due to the RNA polymerase II “slippage”. The accumulation of UBB+1 has been linked to ubiquitin-proteasome system (UPS) dysfunction and neurodegeneration. Alzheimer’s disease (AD) is defined as a progressive neurodegeneration and aggregation of amyloid-? peptides (A?) is a prominent neuropathological feature of AD. In our previous study, we found that yeast cells expressing UBB+1 at lower level display an increased resistance to cellular stresses under conditions of chronological aging. In order to examine the molecular mechanisms behind, here we performed genome-wide transcriptional analyses and molecular/cellular biology assays. We found that low UBB+1 expression activated the autophagy pathway, increased vacuolar activity, and promoted transport of autophagic marker ATG8p into vacuole. Furthermore, we introduced low UBB+1 expression to our humanized yeast AD models, that constitutively express A?42 and A?40 peptide, respectively. The co-expression of UBB+1 with A?42 or A?40 peptide led to reduced intracellular A? levels, ameliorated viability, and increased chronological life span. In an autophagy deficient background strain (atg1?), intracellular A? levels were not affected by UBB+1 expression. Our findings offer insights for reducing intracellular A? toxicity via autophagy-dependent cellular pathways under low level of UBB+1 expression.
Restoration of aged hematopoietic cells by their young counterparts through instructive microvesicles release
Steven J. Greco1, * , Seda Ayer1, * , Khadidiatou Guiro1, * , Garima Sinha1,2 , Robert J. Donnelly3 , Markos H. El-Far1,2 , Lauren S. Sherman1,2 , Yannick Kenfack1,2 , Sri Harika Pamarthi1 , Marina Gergues1,2 , Oleta A. Sandiford1,2 , Michael J. Schonning2 , Jean-Pierre Etchegaray3 , Pranela Rameshwar1
doi : 10.18632/aging.203689
Volume 13, Issue 21, pp 23981—24016
This study addresses the potential to reverse age-associated morbidity by establishing methods to restore the aged hematopoietic system. Parabiotic animal models indicated that young secretome could restore aged tissues, leading us to establish a heterochronic transwell system with aged mobilized peripheral blood (MPB), co-cultured with young MPB or umbilical cord blood (UCB) cells. Functional studies and omics approaches indicate that the miRNA cargo of microvesicles (MVs) restores the aged hematopoietic system. The in vitro findings were validated in immune deficient (NSG) mice carrying an aged hematopoietic system, improving aged hallmarks such as increased lymphoid:myeloid ratio, decreased inflammation and cellular senescence. Elevated MYC and E2F pathways, and decreased p53 were key to hematopoietic restoration. These processes require four restorative miRs that target the genes for transcription/differentiation, namely PAX and phosphatase PPMIF. These miRs when introduced in aged cells were sufficient to restore the aged hematopoietic system in NSG mice. The aged MPBs were the drivers of their own restoration, as evidenced by the changes from distinct baseline miR profiles in MPBs and UCB to comparable expressions after exposure to aged MPBs. Restorative natural killer cells eliminated dormant breast cancer cells in vivo, indicating the broad relevance of this cellular paradigm - preventing and reversing age-associated disorders such as clearance of early malignancies and enhanced responses to vaccine and infection.
Low-protein diet applied as part of combination therapy or stand-alone normalizes lifespan and tumor proliferation in a model of intestinal cancer
Alina Proske1 , Judith Bossen1,2 , Jakob von Frieling1 , Thomas Roeder1,2
doi : 10.18632/aging.203692
Volume 13, Issue 21, pp 24017—24036
Tumors of the intestinal tract are among the most common tumor diseases in humans, but, like many other tumor entities, show an unsatisfactory prognosis with a need for effective therapies. To test whether nutritional interventions and a combination with a targeted therapy can effectively cure these cancers, we used the fruit fly Drosophila as a model. In this system, we induced tumors by EGFR overexpression in intestinal stem cells. Limiting the amount of protein in the diet restored life span to that of control animals. In combination with a specific EGFR inhibitor, all major tumor-associated phenotypes could be rescued. This form of treatment was also successful in a real treatment scenario, which means when they started after the full tumor phenotype was expressed. In conclusion, reduced protein administration can be a very promising form of adjuvant cancer therapy.
MiRNA-30e downregulation increases cancer cell proliferation, invasion and tumor growth through targeting RPS6KB1
Lin Wang1,2 , Xiang-Bo Ji1 , Li-Hong Wang1 , Zhong-Kun Xia2 , Yun-Xia Xie2 , Wen-Jing Liu3 , Jian-Ge Qiu2 , Bing-Hua Jiang3 , Ling-Zhi Liu4
doi : 10.18632/aging.203665
Volume 13, Issue 21, pp 24037—24049
Human esophagus carcinoma (EC) is one of the most common malignant tumors, especially in Africa and Asia including China. In EC initiation and progression, genetic and epigenetic aberrations have been reported to play a major role, but the underlying molecular mechanisms are largely unknown. In this study, the miR-30e levels were analyzed in human EC tissues and TCGA databases, and the results demonstrated that miR-30e expression in EC tissues was significantly decreased compared to adjacent normal tissues. To further investigate the role of miR-30e in cancer cells, we found that forced expression of miR-30e dramatically inhibited cell proliferation, invasion, tube formation, and colony formation of cancer cells. To determine the underlying mechanism of miR-30e, we found that RPS6KB1 was a direct target of miR-30e by binding to its 3?-UTR, which was verified by luciferase activity assay using reporters with wild-type miR-30e and its seed sequence mutant constructs and Western blotting assay. In vivo experiment showed that miR-30e overexpression significantly inhibited tumor growth and decreased RPS6KB1 expression in xenografts. In EC, high expression of RPS6KB1 in tumor tissues indicated poor prognosis of patients with less survival rate. High levels of RPS6KB1 and low levels of miR-30e closely correlated poor survival of patients with several other types of cancer. These findings show that miR-30e and its target RPS6KB1 are important in cancer development and clinical outcomes, and miR-30e/RPS6KB1 is a potential future therapeutic pathway for EC intervention.
Identification of KIF4A as a prognostic biomarker for esophageal squamous cell carcinoma
Lingwei Wang1,2, * , Gang Liu2, * , Enkhbat Bolor-Erdene4 , Qinchuan Li2 , Yunqing Mei3,4 , Lei Zhou3
doi : 10.18632/aging.203585
Volume 13, Issue 21, pp 24050—24070
Esophageal squamous cell carcinoma (ESCC) is the most common and aggressive tumor worldwide, and the long-term survival of these patients remains poor. Three databases (GSE17351, GSE20347, and GSE100942) were obtained from Gene Expression Omnibus, and 193 differentially expressed genes including 56 upregulated and 137 downregulated genes were identified by paired test using limma R package. Then, functional enrichments by gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed these genes were mainly related protein digestion and absorption, and IL-17 signaling pathway. We then constructed a protein-protein interaction network and cytoHubba module to determine the six hub genes and overall survival analysis of the six hub genes were evaluated by UALCAN and GEPIA2 analysis. Ultimately, the experimental results confirmed the KIF4A was overexpressed in the ESCC tissues and cell lines compared with the normal esophageal mucosal tissues and was linked to poor prognosis. Moreover, we also revealed that KIF4A facilitates proliferation, cell cycle, migration, and invasion of ESCC in vivo and in vitro. Overall, these findings demonstrated that KIF4A could serve as diagnostic and prognostic biomarkers and may help facilitate therapeutic targets in ESCC patients.
LncRNA MIR31HG is induced by tocilizumab and ameliorates rheumatoid arthritis fibroblast-like synoviocyte-mediated inflammation via miR-214-PTEN-AKT signaling pathway
Liang Cao1,2, * , Haifeng Jiang3, * , Jing Yang1, * , Jun Mao2 , Guofeng Wei4 , Xiangyun Meng2 , Hongmei Zang1
doi : 10.18632/aging.203644
Volume 13, Issue 21, pp 24071—24085
Fibroblast-like synoviocytes (FLS) obtained from the joint synovium of rheumatoid arthritis (RA) patients exhibit hyperplasia and aggressive inflammatory phenotypes. This study was designed to explore the anti-inflammatory mechanism of IL-6R inhibitor, tocilizumab, in FLS-mediated inflammation in RA from the perspective of non-coding RNAs (ncRNAs). To this end, we sorted primary FLS obtained from the synovium of patients with RA and cultured them in vitro. The cells were then treated with tocilizumab and subjected to lncRNA- and miRNA-seq to identify the ncRNAs regulated by tocilizumab treatment using bioinformatic analysis and experimental verification. Tocilizumab treatment enhanced the expression of lncRNA MIR31HG and reduced that of micoRNA-214 (miR-214). In addition, miR-214 activated the AKT signaling pathway by directly targeting MIR31HG and PTEN. In addition, the tocilizumab-MIR31HG-miR-214-PTEN-AKT axis regulated the proliferation, migration, and production of inflammatory molecules and matrix metalloproteinases (MMPs) in RA-FLS. Furthermore, co-culture experiments showed that this axis could inhibit the inflammatory phenotype of macrophages and protect chondrocytes. In summary, our study shows that tocilizumab suppresses RA-FLS inflammation by regulating the MIR31HG-miR-214-PTEN-AKT pathway, and presents new insights on RA pathogenesis and potential targets for RA therapy.
Identification of the function and mechanism of m6A reader IGF2BP2 in Alzheimer’s disease
Yanyao Deng1 , Hongwei Zhu2 , Le Xiao1 , Chao Liu1 , Ya-Lin Liu2,3, & , Wenzhe Gao2
doi : 10.18632/aging.203652
Volume 13, Issue 21, pp 24086—24100
Alzheimer’s disease, the most common form of dementia in the elderly, is a kind of neurodegenerative disease. However, its pathogenesis and diagnosis remain unclear. M6A is related to nervous system development and neurodegenerative diseases. Here in this study, using multiple RNA-seq datasets of Alzheimer’s brain tissues, along with bioinformatic analysis, we innovatively found that m6A reader protein IGF2BP2 was abnormally highly expressed in Alzheimer’s patients. After compared between Alzheimer’s and normal brain samples, and between IGF2BP2- high and IGF2BP2- low subgroups of Alzheimer’s patients, we took the shared differentially expressed genes as the relevant gene sets of IGF2PB2 affecting Alzheimer’s disease occurrence for subsequent analysis. Then, weight gene correlation analysis was conducted and 17 functional modules were identified. The module that most positively correlated with Alzheimer’s disease and IGF2PB2-high subgroups were mainly participated in ECM receptor interaction, focal adhesion, cytokine-cytokine receptor interaction, and TGF-beta signaling pathway. Afterwards, a hub gene-based model including 20 genes was constructed by LASSO regression and validated by ROC curve for Alzheimer diagnosis. Finally, we preliminarily elucidated that IGF2BP2 could bind with mRNAs in a m6A-dependent manner. This study first elucidates the pathogenic role of IGF2BP2 in Alzheimer’s disease. IGF2BP2 and its relevant m6A modifications are potential to be new diagnostic and therapeutic targets for Alzheimer’s patients.
Curcumol inhibits malignant biological behaviors and TMZ-resistance in glioma cells by inhibiting long noncoding RNA FOXD2-As1-promoted EZH2 activation
Xuyang Lv1, * , Jiangchuan Sun1, * , Linfeng Hu1 , Ying Qian1 , Chunlei Fan1 , Nan Tian1
doi : 10.18632/aging.203662
Volume 13, Issue 21, pp 24101—24116
Currently, conventional treatment is not sufficient to improve the survival of glioma patients. Hence, adopting novel personalized treatment programs is imperative. Curcumol, a Chinese herbal medicine extract from the roots of Rhizoma Curcumae, has attracted significant interest due to its beneficial pharmacological activities. The current study revealed that curcumol inhibited the proliferation, metastasis, self-renewal ability, and TMZ resistance in glioma cells in vitro and in vivo. Next, the potential molecular mechanisms of curcumol in inhibiting glioma were investigated. We found that the long non-coding RNA (lncRNA) FOXD2-As1 might contribute to the effects of curcumol on glioma cells. Enforced expression of FOXD2-As1 attenuated the curcumol-induced reduction in glioma cell proliferation, metastasis, self-renewal ability, and TMZ resistance. Moreover, the forced expression of FOXD2-As1 reversed the inhibitory effect of curcumol on the binding ability of EZH2 and H3K27me3 modification in the promoter regions of anti-oncogenes. Our results showed for the first time that curcumol is effective in inhibiting malignant biological behaviors and TMZ-resistance of glioma cells by suppressing FOXD2-As1-mediated EZH2 activation. Our study offers the possibility of exploiting curcumol as a promising therapeutic agent for glioma treatment and may provide an option for the clinical application of this natural herbal medicine.
Integrated analysis of expression, prognostic value and immune infiltration of GSDMs in hepatocellular carcinoma
Kuan Hu1 , Zhijie Xu2 , Lei Yao1 , Yuanliang Yan3,4 , Lei Zhou5 , Juanni Li2
doi : 10.18632/aging.203669
Volume 13, Issue 21, pp 24117—24135
Six Gasdermins (GSDM) family members participate in various biological processes especially pyroptosis, as well as in the initiation and development of many types of cancer. However, the systematic analysis of the GSDM family in hepatocellular carcinoma (HCC) is lacking. In this study, several bioinformatics databases were recruited to analyze the roles of the GSDMs in differential expression, prognostic correlation, functional enrichment exploration, immune modulation, genetic alterations, and methylated modification in patients with HCC. Consequently, the mRNA expression of all the six GSDMs was accordantly increased in HCC, while only the protein expressions of GSDMB, GSDMD, and GSDME were apparently increased in HCC tissue. The expression of all the GSDMs (except GSDMA) was significantly higher in tumor stage 1–3 subgroups, compared with that in normal subgroups. Higher GSDME expression was significantly associated with shorter overall survival (OS) and disease specific survival (DSS) in patients with HCC. GSDMD had the highest genetic alteration rate among the GSDMs. The three signal pathways which were most likely related to GSDMs-associated molecules were the cell adhesion, growth regulation, and hormone metabolic process. The majority of GSDMs members were positively correlated with the infiltration of B cells, neutrophils, and dendritic cells, however negatively correlated with macrophage. All of the six GSDM members showed remarkably decreased methylation levels in HCC tissues. In conclusion, the GSDM family (especially GSDME) had the potential to become essential biomarkers to better improve the diagnosis and prognosis of HCC, as well as provided insight for the development of therapeutic targets.
Mutations in DNA damage response pathways as a potential biomarker for immune checkpoint blockade efficacy: evidence from a seven-cancer immunotherapy cohort
Wenjing Zhang1, * , Liwen Zhang1, * , Hao Jiang1 , Yuting Li2 , Suzhen Wang1 , Qinghua Wang1
doi : 10.18632/aging.203670
Volume 13, Issue 21, pp 24136—24154
Recently several studies have demonstrated the implications of mutations in DNA damage response (DDR) pathways for immune checkpoint blockade (ICB) treatment. However, smaller sample sizes, lesser cancer types, and the lack of multivariate-adjusted analyses may produce unreliable results. From the Memorial Sloan-Kettering Cancer Center (MSKCC) cohort, we curated 1363 ICB-treated patients to evaluate the association of DDR mutations with immunotherapy prognosis. Besides, 4286 ICB-treated-naive patients from the Cancer Genome Atlas (TCGA) cohort were used to explore the intrinsic prognosis of DDR mutations. Factors in the microenvironment regarding DDR mutations were also assessed. We found that patients with DDR mutations exhibited a significantly prolonged immunotherapy overall survival via multivariate Cox model in the MSKCC cohort (HR: 0.70, P < 0.001). Specific cancer analyses revealed that patients with DDR mutations could obtain the better ICB prognosis in bladder cancer and colorectal cancer (HR: 0.59 [P = 0.034] and 0.33 [P = 0.006]). Stratified analyses showed that age >60, male gender, high mutation burden, and PD-1/PD-L1 treatment were the positive conditions for ICB survival benefits of DDR mutations (all P < 0.01). Mutations of 4 DDR genes, including MRE11A, MSH2, ATM, and POLE could predict favorable ICB prognoses (all P < 0.01). A better immune microenvironment was observed in DDR mutated patients. Mutations in DDR pathways or single DDR genes were associated with preferable ICB efficacy in specific cancers or subpopulations. Findings from our study would provide clues for tailing clinical trials and immunotherapy strategies.
Development of an immune-related signature for predicting survival outcome and immunotherapy response in osteosarcoma
Qinghua Wang1, * , Wenjing Zhang1, * , Yuxian Guo1 , Yuting Li2 , Kaifeng Fu3
doi : 10.18632/aging.203671
Volume 13, Issue 21, pp 24155—24170
Osteosarcoma (OS) is the most common bone cancer, mainly diagnosed in children and adolescents. So far, no reliable molecular biomarkers have been identified to effectively evaluate OS prognosis and immune infiltration. Herein, we curated transcriptome profiles and clinical information from the publicly available OS cohorts to establish an immune-related prognostic signature. Besides, immunotherapeutic cohorts of urothelial cancer and melanoma patients were also employed to infer immunotherapy prediction roles of the identified signature. Lymphocytes infiltration, immune response-related pathways and signatures in the microenvironment were assessed according to distinct risk subgroups. Based on the univariate Cox analysis and further feature selection implemented by the LASSO regression model in the TARGET cohort, a 21-immune-gene signature was identified by combing the expression values and corresponding coefficients. We observed that the low-risk score of this signature was significantly linked with the preferable survival outcome (Log-rank test P < 0.001). The consistent results of better prognoses of the low-risk group were also obtained in subsequent two validation cohorts. Immunology analyses showed that favorable immune infiltration and elevated enrichment of immune response signals may contribute to the better outcome of the low-risk OS subgroup. The immunotherapeutic efficacy analyses demonstrated that low-risk patients harbored significantly enhanced response rates and improved immunotherapy survival outcomes. Together, our established signature could evaluate survival risk and represent the immune microenvironment status of OS, which promotes precision treatment and provides a potential biomarker for prognosis prediction and immunotherapy efficacy assessment.
LncRNA OTUD6B-AS1 promotes paclitaxel resistance in triple negative breast cancer by regulation of miR-26a-5p/MTDH pathway-mediated autophagy and genomic instability
Peng-Ping Li1 , Rong-Guo Li1 , Yu-Qing Huang1 , Jin-Pian Lu2 , Wei-Jun Zhang1 , Zhen-Yu Wang1
doi : 10.18632/aging.203672
Volume 13, Issue 21, pp 24171—24191
Genomic instability (GIN) is pivotal in regulating tumor drug resistance, which blocked the treatment of triple negative breast cancer (TNBC). Although recent studies implied that non-coding RNA (ncRNA)-mediated autophagy abolishment promoted tumorigenesis by up-regulation of GIN, autophagy was known as a risk factor in tumor drug resistance. However, previous study also pointed that up-regulation of autophagy promoted GIN. Therefore, the relationship between autophagy and GIN is not clear, and more work is needed. And, if an ncRNA is identified to be a co-regulator of autophagy and GIN, it will be a potential therapy target of chemotherapy resistance in TNBC. In our study, we recognized both autophagy-GIN-associated microRNA (mi-26a-5p) by big data analysis, which was prognosis-correlated in breast cancer. Next, we identified the up-stream regulators (long non-coding RNA, lncRNA) and down-stream targets of miR-26a-5p by bioinformatics analysis (online public databases). Finally, we established lncRNA OTUD6B-AS1/miR-26a-5p/MTDH signaling pathway, and verified their functions by cytological, molecular biological and zoological experiments. In general, our study found (1) miR-26a-5p was a protective factor of breast cancer, while OTUD6B-AS1 and MTDH were risk factors; (2) OTUD6B-AS1 was the up-stream regulator of miR-26a-5p verified by luciferase; (3) up-regulation of miR-26a-5p and down-regulation of MTDH promoted cellular cytotoxicity of paclitaxel (PTX) in vitro and in vivo. (4) down-regulation of miR-26a-5p, overexpression of MTDH and OTUD6B-AS1 promoted autophagy and DNA damage; (5) up-regulation of OTUD6B-AS1 and MTDH inhibited DNA damage response (DDR) by inhibiting the phosphorylated activation of RAD51, ATR and ATM.
Association of frailty and chemotherapy-related adverse outcomes in geriatric patients with cancer: a pilot observational study in Taiwan
Ya-Wen Ho1,2 , Woung-Ru Tang2 , Shih-Ying Chen2 , Shu-Hui Lee3 , Jen-Shi Chen1 , Yu-Shin Hung1 , Wen-Chi Chou1
doi : 10.18632/aging.203673
Volume 13, Issue 21, pp 24192—24204
With the rapid growth of the elderly population and the increasing incidence of cancer, an increasing number of geriatric patients are receiving cancer treatment, making the selection of appropriate treatment an important issue. Increasing studies have confirmed that frailty can predict adverse outcomes in geriatric patients with cancer after treatment, but local data from Taiwan are lacking. Therefore, this study aimed to investigate the correlation between frailty and chemotherapy-related adverse outcomes in geriatric patients with cancer.
YTH domain family: potential prognostic targets and immune-associated biomarkers in hepatocellular carcinoma
Miaomiao Liu1 , Zijin Zhao2 , Yuan Cai3 , Peng Bi3 , Qiuju Liang4 , Yuanliang Yan4,5 , Zhijie Xu3
doi : 10.18632/aging.203674
Volume 13, Issue 21, pp 24205—24218
Hepatocellular carcinoma (HCC) is the most common high malignancy with insidious onset, invasive fast-growing, high recurrence rate and fatality. YTH domain family plays essential roles in development of HCC. However, the biological function of YTH domain family in HCC have not been clarified. Here, through evaluating the expression profiles of YTH domain family, we found that upregulated YTHDF1 might be more significant and valuable in development and progression of HCC. There was a strong correlation between YTHDC1, YTHDF1 and YTHDF2 and pathological stage of HCC patients. Kaplan-Meier plotter revealed that HCC patients with high level of YTHDF1 and YTHDF2 were highly related to a shorter overall survival time, and low level of YTHDF1 (p = 0.0017) has an important association with a longer progression-free survival time. Genetic alterations using cBioPortal revealed that the alteration rates of YTHDF3 were the highest. We also found that the functions of YTH domain family were linked to several cancer-associated pathways, including peptidyl-serine modification, peptidyl-tyrosine modification and negative regulation of cellular component movement. TIMER database indicated that the YTH domain family had a strong relationship with the infiltration of six types of immune cells (macrophages, neutrophils, CD8+ T-cells, B-cells, CD4+ T-cells and dendritic cells). Next, Ualcan databases revealed that the global methylation levels of YTHDC1 was higher in HCC patients, while YTHDF2 was lower in HCC patients. In conclusion, our findings will enhance the understanding of YTH domain family in HCC pathology, and provide novel insights into YTH-targeted therapy for HCC patients.
Construction and external validation of a 5-gene random forest model to diagnose non-obstructive azoospermia based on the single-cell RNA sequencing of testicular tissue
Ranran Zhou1,2 , Xianyuan Lv1,2 , Tianle Chen1,2 , Qi Chen1,2 , Hu Tian1,2 , Cheng Yang1,2 , Wenbin Guo1,2 , Cundong Liu1,2
doi : 10.18632/aging.203675
Volume 13, Issue 21, pp 24219—24235
Non-obstructive azoospermia (NOA) is among the most severe factors for male infertility, but our understandings of the latent biological mechanisms remain insufficient. The single-cell RNA sequencing (scRNA-seq) data of 432 testicular cells isolated from the patient with NOA was analyzed, and the cell samples were grouped into 5 cell clusters. A sum of 455 cell markers was identified and then included in the protein-protein interaction network. The Top 5 most critical genes in the network, including CCT8, CDC6, PSMD1, RPS4X, RPL36A, were selected for the diagnosis model construction through the random forest (RF). The RF model was a strong classifier for NOA and obstructive azoospermia (OA), which was validated in the training cohort (n = 58, AUC = 1) and external validation cohort (n = 20, AUC = 0.9). We collected the seminal plasma samples and testicular biopsy samples from 20 OA and 20 NOA cases from the local hospital, and the gene expression was detected via Real-Time quantitative Polymerase Chain Reaction (RT-qPCR) and Immunohistochemistry. The RF model also exhibited high accuracy (AUC = 0.725) in the local cohort. In summary, a novel gene signature was developed and externally validated based on scRNA-seq analysis, providing some new biomarkers to uncover the underlying mechanisms and a promising clinical tool for diagnosis in NOA.
The first central precocious puberty proteomic profiles revealed multiple metabolic networks and novel key disease-associated proteins
Chunlin Wang1 , Qingqing Chen1 , Ke Yuan1 , Minfei He1 , Jianfang Zhu1 , Yanlan Fang1 , Jianhong Hu2 , Qingfeng Yan1,3
doi : 10.18632/aging.203676
Volume 13, Issue 21, pp 24236—24250
Though central precocious puberty (CPP) as a disease that seriously affects the development of a child is increasing year by year, treatment options remain limited and is the same as the 1980s’ method. These are mainly due to the complex pathogenesis of central precocious puberty. Therefore, systems biology approach to identify and explore the multiple factors related to the pathogenesis of central precocious puberty is necessary. Our data established the first proteome profile of CPP revealed 163 down-regulated and 129 were up-regulated differentially expressed proteins. These altered proteins were primarily enriched in three metabolic process including energy metabolism, amino acid metabolism and nitrogenous base metabolism. The identified altered members of the metabolic signaling are valuable and potential novel therapeutic targets of central precocious puberty.
A prognostic fibroblast-related risk signature in colorectal cancer
Hao Xu1,2 , Yisheng Pan1
doi : 10.18632/aging.203677
Volume 13, Issue 21, pp 24251—24270
Colorectal cancer (CRC) is the third most common cancer in the world. The accessibility of the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus data allows the prognostic evaluation of CRC. Fibroblasts play a key role in the development and progression of tumors while fibroblast-related risk signature in CRC patients has rarely been mentioned. In this study, TCGA data was classified into high-fibroblast and low-fibroblast groups according to the median of fibroblast content. Among 3845 differentially expressed genes between two groups, 14 prognostic genes commonly expressed in GSE39582 and TCGA were identified by LASSO-COX analysis. Then we established a fibroblast-related risk signature in TCGA training group and validated in the GSE39582 testing group. The risk score was significantly associated with the overall survival (OS), and the poor prognosis of patients in high-risk group might relate to the immune cell infiltration in the tumor microenvironment, epithelial-mesenchymal transition, and extracellular matrix related processes. Overall, we proved that the fibroblast-related signature could predict the prognosis of patients which might shed light on the treatment of CRC.
Immunological and clinical immunotherapy implications of NLRP3 mutations in melanoma
Qinghua Wang1, * , Juncheng Lyu1, * , Wenjing Zhang1 , Fuyan Shi1 , Yanfeng Ren1 , Qian Mao1 , Yujie Liu1 , Yuting Li2 , Suzhen Wang1
doi : 10.18632/aging.203678
Volume 13, Issue 21, pp 24271—24289
Recent studies have demonstrated the role of Nod-like receptor protein 3 (NLRP3) inflammasome in promoting melanoma progression. Immune checkpoint inhibitors (ICI) treatment dramatically extended the survival outcomes for advanced melanoma patients. Nevertheless, immunologic and immunotherapy implications of NLRP3 mutations in melanoma were obscure. Herein, we utilized publicly genomic data of 750 melanoma patients to explore the association of NLRP3 mutations with immunologic and genomic features. In addition, we curated 336 advanced/metastatic melanoma patients treated with ICI agents from 6 published studies to analyze the response rate and survival outcome in relation to NLRP3 mutations. We observed that patients with NLRP3 mutations had a significantly higher tumor mutation burden (P < 0.001) and neoantigen burden (P < 0.001). Moreover, significantly lower tumor heterogeneity (P = 0.048) and purity (P = 0.022) were also observed in this mutated subgroup. Elevated infiltration of immune-response cells, decreased enrichment of immune-suppressive cells, and immune response-related circuits were markedly enriched in patients with NLRP3 mutations. In the pooled ICI-treated cohort, NLRP3 mutations were linked with the higher response rate (P = 0.031) and preferable survival outcome (P = 0.006). NLRP3 mutations were identified to associate with the elevated mutational burden, favorable immune infiltration, and preferable ICI efficacy. Findings derived from our study suggest that NLRP3 mutations may serve as a potential biomarker for evaluating melanoma immunotherapy response.
Decoding the chemical composition and pharmacological mechanisms of Jiedu Tongluo Tiaogan Formula using high-performance liquid chromatography coupled with network pharmacology-based investigation
Qi Zhang1, * , Chunli Piao2, *,& , Wenqi Jin1 , De Jin3 , Han Wang3 , Cheng Tang1 , Xiaohua Zhao2 , Naiwen Zhang2 , Shengnan Gao2 , Fengmei Lian3, &
doi : 10.18632/aging.203679
Volume 13, Issue 21, pp 24290—24312
Type 2 diabetes mellitus (T2DM), a chronic low-grade inflammatory disease with high morbidity and mortality, is a serious threat to public health. Previously we demonstrated that a traditional Chinese medicine formulation, Jiedu Tongluo Tiaogan Formula (JDTL), exerted a favorable hypoglycemic effect due to unknown molecular mechanisms involving interactions among JDTL compounds and various cellular components. This study aimed to explore JDTL mechanisms for alleviating hyperglycemia using an integrated strategy incorporating system pharmacology, bioinformatics analysis, and experimental verification. This strategy entailed initial elucidation of JDTL chemical composition using fingerprint analysis via high performance liquid chromatography (HPLC). Next, functions of putative shared target genes and associated pathways were deduced using GO and KEGG pathway enrichment and molecular docking analyses. Ultimately, targets associated with JTDL anti-T2DM effects were found to be functionally associated with biological functions related to lipopolysaccharide and cytokine receptor binding. These results implicated PI3K-Akt signaling pathway involvement in JDTL anti-T2DM effects, as this pathway had been previously shown to play significant roles in glucose and lipid metabolism-related diseases. Furthermore, addition of JDTL to INS-1 and HepG2 cell cultures stimulated cellular mRNA-level and protein-level expression leading to enhanced production of IRS1, Akt, and PI3K. In summary, here JDTL bioactive ingredients, potential targets, and molecular mechanisms underlying JDTL anti-T2DM effects were identified using a multi-component, multi-target, and multi-channel analytical approach, thus providing an important scientific foundation to facilitate development of new drugs mechanistic strategies for preventing and treating T2DM.
Establishment of a tumor immune microenvironment-based molecular classification system of breast cancer for immunotherapy
Xiaobo Zheng1,2 , Li Li3 , Chune Yu2 , Jiqiao Yang2 , Yujie Zhao2 , Chao Su2 , Jing Yu2 , Mingqing Xu1,4
doi : 10.18632/aging.203682
Volume 13, Issue 21, pp 24313—24338
Antitumor immunotherapy can enable promising and durable responses following their clinical application. However, heterogeneity in the tumor immune microenvironment leads to differences in the individual response rates. In this study, we identified novel immune-related molecular subclasses of breast cancer using a non-negative matrix factorization analysis. We enrolled 4184 patients with breast cancer, including 1104 patients from The Cancer Genome Atlas as a training cohort and 3080 patients from another four independent datasets as validation cohorts. In the training cohort, 36.9% of patients who exhibited significantly higher immunocyte infiltration and enrichment of immune response-associated signatures were categorized into an immune class, which was confirmed by probing the expression of immunocyte markers (CD3, CD19, and CD163). Within the immune class, 53.3% of patients belonged to an immune-suppressed subclass, characterized by the activation of stroma-related signatures and immune-suppressive cells. The remaining patients in the immune class were allocated to an immune-activated subclass. The interferon-? and granzyme B levels were higher in the immune-activated subclass, whereas the transforming growth factor-?1 and programmed cell death-1 (PD-1) levels were higher in the immune-suppressed subclass. The established molecular classification system was recapitulated in validation cohorts. The immune-activated subclass was predicted to have a better response to anti-PD-1 immunotherapy. The immune-related subclasses were associated with differences in copy number alterations, tumor mutation burden, neoantigens, tumor-infiltrating lymphocyte enrichment, PD-1/programmed death-ligand 1 expression, mutation landscape, and various infiltration immunocytes. Overall, we established a novel immune-related molecular classification of breast cancer, which may be used to select candidate patients for immunotherapy.
Deletion of miR-15a inhibited glioma development via targeting Smad7 and inhibiting EMT pathway
Yanfeng Guo1 , Xiaopeng Gao1 , Shien An1 , Xin Li1 , Lekun Pan1 , Hongyan Liu2 , Jixiang Liu1 , Jianzhou Gao1 , Zhihuang Zhao3 , Gang Li3 , Yonggang Han3 , Yabin Li3 , Zhisheng Ji3
doi : 10.18632/aging.203684
Volume 13, Issue 21, pp 24339—24348
In the present study, we found the expression of miR-15a-5p (miR-15a) was increased in glioma tissues, and we further explore the underlying mechanism of miR-15a in glioma progression. Microarray analysis used to identify the differentially expressed microRNAs (miRNAs) in glioma tissues. The expression of miR-15a in glioma tissues and cell lines was tested by qRT-PCR. Luciferase assay was used to determine the binding between miR-15a and Smad7. Wound healing and transwell assay were used to examine the role of miR-15a/Smad7 in SHG139 cells. Western blot was used to detect the protein level of Smad7 and epithelial-mesenchymal transition (EMT) markers. A tumor formation model in nude mice was established to measure the role of miR-15a in vivo. MiR-15a was significantly increased in glioma tissues and cells, which indicated a poor prognosis of glioma patients. MiR-15a mimics induced miR-15a level in SHG139 cells, and promoted the malignancy of SHG139 cells, while miR-15a inhibitor showed the opposite effects. Luciferase assay indicated that Smad7 was the direct target of miR-15a, and Smad7 was down-regulated in glioma tissues. Functional experiments revealed that miR-15a inhibitor inhibited the EMT pathway and the migration and invasion of glioma cells, but the silencing of Smad7 reversed the effects of miR-15a inhibitor in EMT pathway and glioma progression. Finally, we performed animal experiments to verify the role of miR-15a in vivo. Present study showed that deletion of miR-15a inhibited the activation of EMT signaling via targeting Smad7, thus suppressed the tumorigenesis and tumor growth of glioma.
A five-lncRNA model predicting overall survival in gastric cancer compared with normal tissues
Congbo Cai1, * , Lei Yang1, * , Xieyan Zhuang2 , Yi He3 , Kena Zhou3
doi : 10.18632/aging.203685
Volume 13, Issue 21, pp 24349—24359
In cancer research, normal tissues adjacent to the tumor are usually defined as controls to compare with tumor samples, in order to screen out cancer-related genes. Although there is no obvious difference in pathology between normal tissues adjacent to the tumor and healthy tissues, there are significant changes at the molecular level. We aim to explore more potential tumor biomarkers using healthy tissues as controls rather than normal tissues adjacent to the tumor.
Polymorphisms in lncRNA MIR2052HG and susceptibility to breast cancer in Chinese population
Hui Yang1 , Qiuyu Sun2,3,4 , Feifei Chong2,3,4 , Xiaoru Jiang2,3,4 , Yanli Wang2,3,4 , Kedi Xu2,3,4 , Yuanlin Zou2,3,4 , Linping Xu5 , Chunhua Song2,3,4
doi : 10.18632/aging.203686
Volume 13, Issue 21, pp 24360—24378
Published studies based on pharmacokinetics have explored the relationship between the lncRNA MIR2052HG and the prognosis of breast cancer (BC) resistance and recurrence. However, the underlying association of MIR2052HG SNPs with BC development remains unclear.
Pyroptosis-related gene mediated modification patterns and immune cell infiltration landscapes in cutaneous melanoma to aid immunotherapy
Jinzhi Meng1 , Xing Huang1 , Yue Qiu1 , Xifan Zheng1 , Junpu Huang1 , Zhenpei Wen1 , Jun Yao1
doi : 10.18632/aging.203687
Volume 13, Issue 21, pp 24379—24401
Tumor occurrence, infiltration, and metastasis are significantly affected by the tumor microenvironment (TME). Increasing evidence has elucidated TME’s clinical significance in prognostic assessment and immunotherapy efficacy. Nonetheless, no studies have reported the potential pyroptosis-related genes (PRGs) function in TME immune cell infiltration. In this study, we systematically analyzed different PRG modification patterns in 685 cutaneous melanoma (CM) cases. We comprehensively explored the relationship between these PRG modification patterns and TME cell infiltration characteristics. Then, we used principal component analysis to construct a pyroptosis scoring system to quantify the PRG modification patterns in each CM patient. Three different PRG modification patterns were identified. Pyroptosis score was confirmed as an independent prognostic factor for CM patients. High pyroptosis score was characterized by high immunophenscore and more lymphocytes infiltration, such as T, B, and NK cells - indicating a strong ability to monitor and clear tumors, which may be responsible for the advantageous survival. Three independent cohorts that received immunotherapy confirmed the significant therapeutic efficacy and clinical benefit in high pyroptosis scores patients. This study revealed that the PRG modification patterns have a crucial effect on the CM complex and diverse microenvironment. Pyroptosis scores might serve as credible predictors of immunotherapy response and prognostic assessment. This provides a new direction for personalized immunotherapy strategies and appropriate immunotherapy candidates screening.
miR-6745-TIMP1 axis inhibits cell growth and metastasis in gastric cancer
Hui Liu1, * , Yuan Xiang1,2, * , Qi-Bei Zong1, * , Xiao-Yu Zhang1 , Zhi-Wen Wang3 , Shi-Qiang Fang2 , Tong-Cun Zhang1 , Xing-Hua Liao1
doi : 10.18632/aging.203688
Volume 13, Issue 21, pp 24402—24416
Tissue inhibitor matrix metalloproteinase 1 (TIMP1) has been reported to act as a tumor oncogene in colon cancer. However, little is known about the biological role of TIMP1 in gastric cancer. In this study, we found that the expression of TIMP1 in GC tissues was upregulated compared with the normal gastric tissues. TIMP1 was confirmed as a direct target of miR-6745 and silencing TIMP1 mimicked the effects of miR-6745 in GC cells. Further mechanism studies have shown that miR-6745 inhibits the Wnt/?-catenin pathway by targeting TIMP1, thereby inhibiting cell proliferation, migration and invasion. In addition, through the analysis of GC tissues, a negative correlation between miR-6745 and TIMP1 was found in 42 GC tissues. Our findings indicate that the miR-6745-TIMP1 axis regulates Wnt/?catenin signaling and participates in GC tumorigenesis and provide a potential therapeutic target for preventing GC progression.
RIP3 Inhibition ameliorates chronic constriction injury-induced neuropathic pain by suppressing JNK signaling
Na He1,2 , Yu-Juan Qu1 , Dan-Yang Li1 , Shou-Wei Yue1
doi : 10.18632/aging.203691
Volume 13, Issue 21, pp 24417—24431
Neuroinflammation is a major contributor to neuropathic pain. Receptor interacting serine/threonine kinase 3 (RIP3) senses cellular stress, promotes inflammatory responses and activates c-Jun N-terminal kinase (JNK) signaling. Here, we assessed the involvement of RIP3-induced JNK signaling in chronic constriction injury (CCI)-induced neuropathic pain. We found that RIP3 inhibitors (GSK’872) and JNK inhibitors (SP600125) not only alleviated the radiant heat response and mechanical allodynia in CCI rats, but also reduced inflammatory factor levels in the lumbar spinal cord. CCI surgery induced RIP3 mRNA and protein expression in the spinal cord. GSK’872 treatment after CCI surgery reduced RIP3 and phosphorylated (p)-JNK expression in the spinal cord, whereas SP600125 treatment after CCI surgery had almost no effect on RIP3. Sinomenine treatment reduced RIP3, p-JNK and c-Fos levels in the spinal cords of CCI rats. These data demonstrated that RIP3 inhibition (particularly via sinomenine treatment) alleviates neuropathic pain by suppressing JNK signaling. RIP3 could thus be a new treatment target in patients with neuropathic pain.
Immune cell and TCR/BCR repertoire profiling in systemic lupus erythematosus patients by single-cell sequencing
Fengping Zheng1 , Huixuan Xu2 , Cantong Zhang2 , Xiaoping Hong3 , Dongzhou Liu3 , Donge Tang2 , Zuying Xiong1, & , Yong Dai2
doi : 10.18632/aging.203695
Volume 13, Issue 21, pp 24432—24448
The immune cells and the repertoire of T cells and B cells play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Exploring their expression and distribution in SLE can help us better understand this lethal autoimmune disease. In this study, we used a single-cell 5’ RNA sequence and single-cell T cell receptor (TCR)/B cell receptor (BCR) to study the immune cells and the repertoire from ten SLE patients and the paired normal controls (NC). The results showed that 9732 cells correspondence to 12 cluster immune cell types were identified in NC, whereas 11042 cells correspondence to 16 cluster immune cell types were identified in SLE. The results demonstrated that neutrophil, macrophage, and dendritic cells were accumulated in SLE by annotating the immune cell types. Besides, the bioinformatics analysis of differentially expressed genes (DEGs) in these cell types indicates their role in inflammation response. In addition, patients with SLE showed increased TCR and BCR clonotypes compared with the healthy controls. Furthermore, patients with SLE showed biased usage of TCR and BCR V(D)J genes. Taken together, we characterized the transcriptome and TCR/BCR immune repertoire profiles of SLE patients, which may provide a new avenue for the diagnosis and treatment of SLE.
Small interfering RNA-induced silencing lncRNA PVT1 inhibits atherosclerosis via inactivating the MAPK/NF-?B pathway
Hong Du1 , Hui Zhang1 , Rong Yang1 , Li Qiao1 , Huiyu Shao1 , Xiaolin Zhang1
doi : 10.18632/aging.203696
Volume 13, Issue 21, pp 24449—24463
Atherosclerosis (AS) is a chronic disease of the arterial wall. The role of lncRNAs in AS has been acknowledged. This study investigated the role of lncRNA plasmacytoma variant translocation 1 (PVT1) in AS via the MAPK/NF-?B pathway. Serum samples were collected from AS and non-AS patients. Serum levels of PVT1, CRP, IL-6, IL-1?, and TNF-? were determined. AS mouse model was established and transfected with si-PVT1. Levels of TG, TC, HDL, LDL, MAPK, NF-?B, MMP-2, MMP-9, TIMP-1, and macrophage content were detected. Human arterial vascular smooth muscle cells (HA-VSMCs) induced by 50 mg/mL oxLDL were transfected with si-PVT1 or oe-PVT1 and added with MAPK inhibitor U0126. Viability, apoptosis, cell cycle, colony formation and DNA replication were assessed. Levels of apoptosis-related proteins were detected. Consequently, PVT1 was highly expressed in AS patients. Silencing PVT1 decreased levels of TG, TC, LDL, IL-6, IL-1?, TNF-?, MMP-2, MMP-9, CRP, TIMP-1, MAPK, and NF-?B, increased HDL, reduced atherosclerotic plaques and macrophage content in mice, inhibited viability, clones and EdU positive rates in HA-VSMCs, but promoted apoptosis and cell cycle arrest. Inhibition of MAPK/NF-?B pathway suppressed proliferation and promoted apoptosis of HA-VSMCs while PVT1 overexpression facilitated AS development. Briefly, silencing PVT1 inhibited AS development by downregulating MAPK/NF-?B pathway.
Propofol suppresses the growth and invasion of cervical carcinoma cells by inhibiting MIR155HG
Xin-Tan Du1 , Xiao-Yan Wang2 , Ying-He Zheng3 , Da-Peng Liu1
doi : 10.18632/aging.203697
Volume 13, Issue 21, pp 24464—24475
Cervical cancer is the most prevalent malignancy worldwide and propofol reportedly has anti-cancer efficiencies. Herein, we tried to address the potential anti-cancer effects of propofol in cervical carcinoma.
Correction for: Decreased gray matter volume and increased white matter volume in patients with neovascular age-related macular degeneration: a voxel-based morphometry study
Yan-Kun Shen1 , Qian-Min Ge1 , Yi-Cong Pan1 , Hui-Ye Shu1 , Li-Juan Zhang1 , Qiu-Yu Li1 , Rong-Bin Liang1 , Yi Shao1 , Yao Yu1, &
doi : 10.18632/aging.203702
Volume 13, Issue 21, pp 24476
