Age-related disease burdens increased over time, and whether plasma peptides can be used to accurately predict age in order to explain the variation in biological indicators remains inadequately understood. Here we first developed a biological age model based on plasma peptides in 1890 Chinese Han adults. Based on mass spectrometry, 84 peptides were detected with masses in the range of 0.6-10.0 kDa, and 13 of these peptides were identified as known amino acid sequences. Five of these thirteen plasma peptides, including fragments of apolipoprotein A-I (m/z 2883.99), fibrinogen alpha chain (m/z 3060.13), complement C3 (m/z 2190.59), complement C4-A (m/z 1898.21), and breast cancer type 2 susceptibility protein (m/z 1607.84) were finally included in the final model by performing a multivariate linear regression with stepwise selection. This biological age model accounted for 72.3% of the variation in chronological age. Furthermore, the linear correlation between the actual age and biological age was 0.851 (95% confidence interval: 0.836-0.864) and 0.842 (95% confidence interval: 0.810-0.869) in the training and validation sets, respectively. The biological age based on plasma peptides has potential positive effects on primary prevention, and its biological meaning warrants further investigation.

Long non-coding RNAs play critical roles in tumorigenesis and the immune process. In this study, RNA sequencing data for 946 glioma samples from The Cancer Genome Atlas and the Chinese Glioma Genome Atlas databases were analyzed to evaluate the prognostic value and function of homeobox A transcript antisense RNA myeloid-specific (HOTAIRM)1. HOTAIRM1 expression was associated with clinical and molecular features of glioma: patients with high HOTAIRM1 expression were more likely to be classified as malignant cases, and elevated HOTAIRM1 level was associated with shorter survival time in subgroups stratified by clinical and molecular features. A multivariate Cox regression analysis showed that HOTAIRM1 was an independent prognostic factor for patient outcome. In vitro experiments revealed that HOTAIRM1 knockdown suppressed the malignant behavior of glioma and increased tumor sensitivity to temozolomide. The results of an in silico analysis indicated that HOTAIRM1 promotes the malignancy of glioma by acting as a sponge for microRNA (miR)-129-5p and miR-495-3p. HOTAIRM1 overexpression was also associated with immune activation characterized by enhanced T cell-mediated immune and inflammatory responses. These results suggest that HOTAIRM1 is a prognostic biomarker and potential therapeutic target in glioma.

With the population aging, age-related sinoatrial node dysfunction (SND) has been on the rise. Sinoatrial node (SAN) degeneration is an important factor for the age-related SND development. However, there is no suitable animal modeling method in this field. Here, we investigated whether D-galactose could induce SAN degeneration and explored the associated mechanism. In vivo, twelve C57BL/6 mice were divided into Control and D-galactose group to receive corresponding treatments. Senescence was confirmed by analyzing the hair and weight; cardiac function was evaluated through echocardiography, cerebral blood flux and serum-BNP; the SAN function was evaluated by electrocardiogram; fibrotic change was evaluated by Masson's trichrome staining and oxidative stress was assessed through DHE staining and serum indicators. Mechanism was verified through immunofluorescence-staining and Western blotting. In vitro, mouse-atrial-myocytes were treated with D-galactose, and edaravone was utilized as the ROS scavenger. Senescence, oxidative stress, proliferation ability and mechanism were verified through various methods, and intuitive evidence was obtained through electrophysiological assay. Finally, we concluded that D-galactose can be used to induce age-related SND, in which oxidative stress plays a key role, causing PITX2 ectopic expression and downregulates SHOX2 expression, then through the downstream GATA4/NKX2-5 axis, results in pacing-related ion channels dysfunction, and hence SND development.

Existing reports identify the involved roles of ZNF139 and its one circular RNA (circRNA), circZNF139, in the progression of various tumors. However, their relevance and function role in bladder cancer (BC) remain largely unexplored. Herein, we aimed to reconnoiter the role and potential mechanism of ZNF139 and circZNF139 in the progression of BC. Firstly, bioinformatics analyses indicated ZNF139 was upregulated in BC tissues and correlated with disease-free survival of BC patients. The subcellular localization and structural analyses of ZNF139 conveyed the possibility of ZNF139 functioning as a transcription factor. Secondly, circZNF139 was validated by bioinformatics analyses and RNase R tests. ZNF139 and circZNF139 were both significantly upregulated in BC cell lines. Functionally, ZNF139/circZNF139 had facilitated effects on the proliferative, clonal, migratory, and invasive potential of BC cells. Mechanistically, GO, KEGG pathway analyses and western blot assays altogether unveiled ZNF139/circZNF139 activated PI3K/AKT pathway in BC cells, supported by the alteration of AKT at phosphorylation level and PI3K at the protein level. Collectively, this work reveals ZNF139 and circZNF139 cooperate closely with each other to promote cell proliferation, migration and invasion via activation of PI3K/AKT pathway in BC.

Exosomes play important roles in proliferation and microenvironment modulation of many types of cancers, including colorectal cancer (CRC). However, the inhibitory effect of CRC cells-derived exosomes in angiogenesis has not been fully discussed. In this study, the roles of microRNA-183-5p (miR-183-5p) in abundant in exosomes secreted from the CRC cells were investigated. Initially, microarray analysis was employed to determine the differentially expressed miRNAs. Exosomes isolated from CRC cells were co-cultured with HMEC-1 cells to explore the role of exosomes in angiogenesis. Further, the effects of CRC cell-derived exosomal miR-183-5p on proliferation, invasion and tube formation abilities of HMEC-1 cells were assessed. The preventative effect of exosomal miR-183-5p in vivo was measured in nude mice. Initially, it was found that FOXO1 was downregulated while miR-183-5p was upregulated in CRC. Additionally, the inhibition of miR-183-5p was suggested to suppress proliferation, invasion and tube formation abilities of HMEC-1 cells through upregulating FOXO1. Then, in vitro assays demonstrated that CRC cell-derived exosomes overexpressing miR-183-5p contributed to an enhanced proliferation, invasion and tube formation abilities of HMEC-1 cells. Furthermore, in vivo experiments confirmed the tumor-promotive effects of CRC cell-derived exosomal miR-183-5p. Collectively, our study demonstrates that the CRC cell-derived exosomes overexpressing miR-183-5p aggravates CRC through the regulation of FOXO1. Exosomes overexpressing miR-183-5p might be a potential treatment biomarker for CRC.

Intervertebral disc degeneration (IDD) is an irreversible aging-associated clinical condition of unclear etiology. Mesenchymal stem cells (MSCs) have the potential to delay IDD, but the mechanisms by which MSCs attenuate senescence-related degeneration of nucleus pulposus cells (NPCs) remain uncertain. The present study employed a three-dimensional (3D) co-culture system to explore the influence of MSCs on NPC degeneration induced by TNF-α in rat cells. We found that co-culture with bone marrow-derived MSCs (BMSCs) reduced senescence-associated β-galactosidase expression, increased cell proliferation, decreased matrix metalloproteinase 9, increased Coll-IIa production, and reduced TGFβ/NF-κB signaling in senescent NPCs. In addition, expression of zinc metallopeptidase STE24 (ZMPSTE24), whose dysfunction is related to premature cell senescence and aging, was decreased in senescent NPCs but restored upon BMSC co-culture. Accordingly, ZMPSTE24 overexpression in NPCs inhibited the pro-senescence effects of TGFβ/NF-κB activation upon TNF-α stimulation, while both CRISPR/Cas9-mediated silencing and pharmacological ZMPSTE24 inhibition prevented those effects. Ex-vivo experiments on NP explants provided supporting evidence for the protective effect of MSCs against NPC senescence and IDD. Although further molecular studies are necessary, our results suggest that MSCs may attenuate or prevent NP fibrosis and restore the viability and functional status of NPCs through upregulation of ZMPSTE24.

Bromodomain-containing protein 4 (BRD4) is overexpressed in thyroid carcinoma, represents as an important therapeutic target. ARV-825 is a novel cereblon-based PROTAC (Proteolysis Targeting Chsimera) compound. It can induce fast and sustained BRD4 protein degradation. Its potential effect in human thyroid carcinoma cells was studied here. In TPC-1 cells and primary human thyroid carcinoma cells, ARV-825 potently inhibited cell viability, proliferation and migration. Furthermore, ARV-825 induced robust apoptosis activation in the thyroid carcinoma cells. ARV-825 induced BRD4 protein degradation and downregulation of its targets, including c-Myc, Bcl-xL and cyclin D1 in thyroid carcinoma cells. It was significantly more potent in inhibiting thyroid carcinoma cells than the known small molecule BRD4 inhibitors. In vivo studies demonstrated that ARV-825 oral administration potently suppressed TPC-1 xenograft tumor growth in severe combined immunodeficient mice. BRD4 protein degradation as well as c-Myc, Bcl-xL and cyclin D1 downregulation were detected in ARV-825-treated TPC-1 tumor tissues. Taken together, ARV-825 induces BRD4 protein degradation and inhibits thyroid carcinoma cell growth in vitro and in vivo.

The vital roles of long noncoding RNAs (lncRNAs) have been implicated in growing number of studies in tumor development. LncRNA CCAT1 has been recognized as associated with tumor development, yet its relation with colorectal cancer (CRC) remains elusive. Our study aimed at elucidating the function and mechanisms of long non-coding RNA CCAT1 in CRC. From a lncRNA profile dataset of 38 pairs of matched tumor-control colon tissues from colorectal patients housed in The Cancer Genome Atlas (TCGA), we detected 10 upregulated and 10 down-regulated lncRNAs in CRC. Fifty cases of CRC patients were enrolled to analyze the correlation between the expression of CCAT1 and clinical pathology. The inverse correlation of expression and target relationship between CCAT1 and miR-181a-5p were verified using qRT-PCR and dual-luciferase reporter gene assay. Cell viability, colony formation ability, aggression and apoptosis were determined by MTT assay, colony formation assay, Transwell and wound healing assays and flow cytometry analysis. Furthermore, Xenograft model was used to show that knockdown of CCAT1 inhibits tumor growth in vivo. The expression of lncRNA CCAT1 was significantly upregulated in CRC tissues. The CCAT1 expression was positively associated with cancer stage (American Joint Committee on Cancer stage, P<0.05). CCAT1 promoted cell proliferation, growth and mobility by targeting miR-181a-5p and the silence of CCAT1 increased the cell apoptosis. Same effect was observed in an in vivo xenograft model, which the tumor size and pro-tumor proteins were significantly diminished by knocking down of CCAT1.

ADAM15 is highly expressed in malignant tumors and is correlated with tumor progression. However, the role of ADAM15 in hepatocellular carcinoma (HCC) remains unclear. In the study, our results indicated that ADAM15 was highly expressed in HCC tissues and cells compared with corresponding tissues and liver cells. Overexpression of ADAM15 was linked to poor prognosis, and was an independent risk factor for HCC prognosis. Besides, analysis of immune infiltration indicated that ADAM15 expression was related to tumor infiltrating lymphocytes based on the TIMER, TISIDB and GEPIA databases. Many immune checkpoint gene expression was associated with ADAM15 expression. Functional enrichment analyses indicated that apoptosis, cell adhesion was enriched. ADAM15 knockdown promoted apoptosis and suppressed proliferation, migration and invasion of liver cancer cells. The findings of western blot showed that ADAM15 knockdown reduced the expression of Bcl-2, Vimentin, N-Cadherin and Snail, and elevated the expression of Bax, E-cadherin and ZO-1. However, overexpression of ADAM15 had the opposite results. Collectively, our findings demonstrated that ADAM15 was connected with poor prognosis of HCC patients, and could be considered as a potential biomarker for the diagnosis and treatment of HCC.

Metabolic syndrome (MetS) is a cluster of health problems that places individuals at higher risk of developing cardiovascular disease, diabetes and stroke. The prevalence of MetS is increasing worldwide. It is also well accepted that genetic and environmental factors play significant roles in the occurrence/development of MetS, but studies exploring genetic factors are still lacking. Here, we aimed to investigate the association of ADIPOQ gene variants with MetS in an elderly Chinese Han population.

Vascular homeostasis abnormalities may involve in doxorubicin induced cardiotoxicity.

The culture supernatant from macrophages overexpressing TRIM59 has a cytotoxic effect on melanoma, but the mechanism remains unclear. To investigate whether deletion of TRIM59 in macrophages affects the metastatic potential of melanoma cells, we polarized control and TRIM59-deficient bone marrow-derived macrophages to the M2 phenotype and collected the respective conditioned media (CM). Exposure to CM from TRIM59-/--M2 cultures significantly promoted migration and invasion by B16-F0 and B16-F10 cells. Cytokine profiling indicated a ~15-fold increase in TNF-α production in CM from TRIM59-/--M2 cultures, and neutralizing TNF-α activity abrogated the referred stimulatory effects on cell motility. Transcriptome analysis revealed significant upregulation of MMP-9 and Madcam1 in melanoma cells exposed to TRIM59-/--M2 CM. Inhibitory experiments determined that these changes were also TNF-α-dependent and mediated by activation of ERK signaling. Independent knockdown of MMP9 and Madcam1 in B16-F10 cells impeded epithelial-mesenchymal transition and inhibited subcutaneous tumor growth and formation of metastatic lung nodules in vivo. These data suggest TRIM59 expression attenuates the tumor-promoting effect of tumor-associated macrophages, most of which resemble the M2 phenotype. Moreover, they highlight the relevance of TRIM59 in macrophages as a potential regulator of tumor metastasis and suggest TRIM59 could serve as a novel target for cancer immunotherapy.

Osteoarthritis (OA) is one of the most painful and widespread chronic degenerative joint diseases and is characterized by destructed articular cartilage and inflamed joints. Previously, our findings indicated that circular RNA ciRS-7 (ciRS-7)/microRNA 7 (miR-7) axis is abnormally expressed in OA, and regulates proliferation, inflammatory responses, and apoptosis of interleukin-1β (IL-1β)-stimulated chondrocytes. However, its underlying role in OA remains unknown. In this study, we first validated cartilage degradation and defection of autophagy in samples of OA patients. IL-1β initially stimulated autophagy of chondrocytes, and ultimately significantly suppressed autophagy. Upregulated ciRS-7/down-regulated miR-7 aggravated IL-1β-induced cartilage degradation, and restrained autophagy in vitro. Gene sequencing and bioinformatics analysis performed on a control group, IL-1β group, and IL-1β+miR-7-mimics group demonstrated that seven of the most significant mRNA candidates were enriched in the interleukin-17 (IL-17) signaling pathway. Increased IL-17A levels were also observed by qRT-PCR and ELISA. In addition, it was revealed that the ciRS-7/miR-7 axis ameliorated cartilage degradation and defection of autophagy by PI3K/AKT/mTOR activation in IL-1β-induced chondrocytes. Furthermore, an OA model was established in rats with medial meniscus destabilization. miR-7-siRNA-expressing lentiviruses alleviated surgical resection-induced cartilage destruction of OA mice, whereas miR-7 mimics worsened the effects. Thus, these findings revealed that the mechanism of the ciRS-7/miR-7 axis involved regulating OA progression and provided valuable directions for OA treatment.

Globally, gastric cancer (GC) is still a major leading cause of cancer-associated deaths. Downregulated desmocollin2 (DSC2) is considered to be closely related to tumor progression. However, the underlying mechanisms of DSC2 in GC progression require further exploration.

Genes related to human longevity have not been studied so far, and need to be investigated thoroughly. This study aims to explore the relationship among ABO gene variants, lipid levels, and longevity phenotype in individuals (≥90yrs old) without adverse outcomes. A genotype-phenotype study was performed based on 5803 longevity subjects and 7026 younger controls from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Four ABO gene variants associated with healthy longevity (rs8176719 C, rs687621 G, rs643434 A, and rs505922 C) were identified and replicated in the CLHLS GWAS data analysis and found significantly higher in longevity individuals than controls. The Bonferroni adjusted p-value and OR range were 0.013-0.020 and 1.126-1.151, respectively. According to the results of linkage disequilibrium (LD) analysis, the above four variants formed a block on the ABO gene (D'=1, r2range = 0.585-0.995). The carriers with genotypes rs687621 GG, rs643434 AX, or rs505922 CX (prange = 2.728 x 10-107-5.940 x 10-14; ORrange = 1.004-4.354) and haplotype CGAC/XGXX (p = 2.557 x 10-27; OR = 2.255) had a substantial connection with longevity, according to the results of genetic model analysis. Following the genotype and metabolic phenotype analysis, it has been shown that the longevity individuals with rs687621 GG, rs643434 AX, and rs505922 CX had a positive association with HDL-c, LDL-c, TC, TG (prange = 2.200 x 10-5-0.036, ORrange = 1.546-1.709), and BMI normal level (prange = 2.690 x 10-4-0.026, ORrange = 1.530-1.997). Finally, two pathways involving vWF/ADAMTS13 and the inflammatory markers (sE-selectin/ICAM1) that co-regulated lipid levels by glycosylation and effects on each other were speculated. In conclusion, the association between the identified longevity-associated ABO variants and better health lipid profile was elucidated, thus the findings can help in maintaining normal lipid metabolic phenotypes in the longevity population.

Heart failure (HF) is a major public health problem worldwide. The development of HF was related to coronary microvessel dysfunction. Whether miRNAs participate in HF by regulating coronary microvessel function remain unclear.

Multiple studies indicate that microRNAs (miRNAs) are involved in diabetes. However, the roles of miRNA in the target organ damages in diabetes remain unclear. This study investigated the functions of miR-320a in diabetic nephropathy (DN). In this study, db/db mice were used to observe the changes in podocytes and their function in vivo, as well as in cultured mouse podocyte cells (MPC5) exposed to high glucose in vitro. To further explore the role of miR-320a in DN, recombinant adeno-associated viral particle was administered intravenously to manipulate the expression of miR-320a in db/db mice. Overexpression of miR-320a markedly promoted podocyte loss and dysfunction in DN, including mesangial expansion and increased levels of proteinuria, serum creatinine and urea nitrogen. Furthermore, MafB was identified as a direct target of miR-320a through AGO2 co-immunoprecipitation, luciferase reporter assay, and Western blotting. Moreover, re-expression of MafB rescued miR-320a-induced podocyte loss and dysfunction by upregulating the expressions of Nephrin and glutathione peroxidase 3 (Gpx3). Our data indicated that miR-320a aggravated renal disfunction in DN by targeting MafB and downregulating Nephrin and Gpx3 in podocytes, which suggested that miR-320a could be a potential therapeutic target of diabetic nephropathy.

Hepatocellular carcinoma (HCC) remains imposing an enormous economic and healthcare burden worldwide. In this present study, we constructed and validated a novel autophagy-related gene signature to predict the recurrence of HCC patients. A total of 29 autophagy-related differentially expressed genes were identified. A five-gene signature (CLN3, HGF, TRIM22, SNRPD1, and SNRPE) was constructed for HCC recurrence prediction. Patients in high-risk groups exhibited a significantly poor prognosis compared with low-risk patients both in the training set (GSE14520 dataset) and the validation set (TCGA and GSE76427 dataset). Multivariate cox regression analysis demonstrated that the 5-gene signature was an independent risk factor for recurrence-free survival (RFS) in HCC patients. The nomograms incorporating 5-gene signature and clinical prognostic risk factors were able to effectively predict RFS. KEGG and GSEA analysis revealed that the high-risk group was enriched with multiple oncology characteristics and invasive-related pathways. Besides, the high-risk group had a higher level of immune cells and higher levels of immune checkpoint-related gene expression in the tumor microenvironment, suggesting that they might be more likely to benefit from immunotherapy. Finally, the immunohistochemistry and cell experiments confirmed the role of SNRPE, the most significant gene in the gene signature. SNRPE was significantly overexpressed in HCC. After SNRPE knockdown, the proliferation, migration and invasion ability of the HepG2 cell line were significantly inhibited. Our study established a novel five-gene signature and nomogram to predict RFS of HCC, which may help in clinical decision-making for individual treatment.

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with a rising prevalence worldwide. Immunotherapy has been shown to improve treatment outcomes for HCC. We aimed to construct a T-cell exhaustion-related gene prognostic model (TEXPM) for HCC and to elucidate the immunologic characteristics and advantages of immunotherapy in T-cell exhaustion-Related Gene-defined HCC groups.