Large-scale epidemiological surveys suggest that hearing loss (HL) is a significant risk factor for dementia. We previously showed that noise-induced HL (NIHL) impairs hippocampal cognitive function and decreases hippocampal neurogenesis and neuronal complexity, suggesting a causal role of HL in dementia. To further investigate the influence of acquired peripheral HL on hippocampal neurogenesis with the aging process as well as the underlying mechanism, we produced NIHL in male CBA/J mice and assessed hippocampal neurogenesis and microglial morphology in the auditory brain and hippocampus at 4 days post-noise exposure (DPN) or 1, 3, 6, or 12 months post-noise exposure (MPN) by immunofluorescence labeling. We found that the age-related decline in hippocampal neurogenesis was accelerated in mice with NIHL. Furthermore, in mice with NIHL, prolonged microglial activation occurred from 1 MPN to 12 MPN across multiple auditory nuclei, while aggravated microglial deterioration occurred in the hippocampus and correlated with the age-related decline in hippocampal neurogenesis. These results suggest that acquired peripheral HL accelerates the age-related decline in hippocampal neurogenesis and that hippocampal microglial degeneration may contribute to the development of neurodegeneration following acquired peripheral HL.

Only a minority of patients clinically benefit from immune checkpoint therapy. Tumor clones with neoantigens have immunogenicity; therefore, they are eliminated by T-cell-mediated immune editing. Identifying neoantigen clones with the ability to induce immune elimination may better predict the clinical outcome of immunotherapy.

Hydrogen sulfide (H2S), an endogenous gaseous signal molecule, regulates many pathologies related to aging. Sirtuin 1 (SIRT1) has been shown to protect against mitochondrial dysfunction and other pathological processes, including premature senescence. This study was aimed to investigate whether and how H2S attenuates senescence and apoptosis of alveolar epithelial cells via a SIRT1-dependent mechanism. Our results showed that treatment with sodium hydrosulfide (NaHS), a donor of H2S, attenuated cigarette smoke extract (CSE)-induced oxidative stress, mitochondrial dysfunction, cellular senescence and apoptosis in A549 cells. This was associated with SIRT1 upregulation. SIRT1 activation by a pharmacological activator, SRT1720, attenuated CSE-induced oxidative stress and mitochondrial dysfunction in A549 cells. While SIRT1 inhibition by EX 527 or silencing by siRNA transfection significantly attenuated or abolished the ability of NaHS to reverse the CSE-induced oxidative stress, mitochondrial dysfunction and the imbalance of mitochondrial fusion and fission. Also, SIRT1 inhibition or silencing abolished the protection of NaHS against CSE-induced cellular senescence and apoptosis. In conclusion, H2S attenuates CSE-induced cellular senescence and apoptosis by improving mitochondrial function and reducing oxidative stress in alveolar epithelial cells in a SIRT1-dependent manner. These findings provide novel mechanisms underlying the protection of H2S against cigarette smoke-induced COPD.

Inflammatory responses are considered to be the critical mechanism underlying particulate matter (PM)-induced development and exacerbation of chronic respiratory diseases. MiR-29b-3p has been found to participate in various biological processes, but its role in PM-induced inflammatory responses was previously unknown. Here, we constructed a miRNA PCR array to find that miR-29b-3p was the most highly expressed in human bronchial epithelial cells (HBECs) exposed to PM. MiR-29b-3p promoted PM-induced pro-inflammatory cytokines (IL-1β, IL-6, and IL-8) expression via inhibiting the AMPK signaling pathway in HBECs. RNA sequencing and luciferase reporter assay identified that miR-29b-3p targeted complement C1q tumor necrosis factor-related protein 6 (C1QTNF6), a protein that protected from PM-induced inflammatory responses via activating the AMPK signaling pathway. In vivo, miR-29b-3p antagomirs delivered via the tail vein prior to PM exposure significantly counteracted PM-induced miR-29b-3p upregulation and C1QTNF6 downregulation in lung tissues. Furthermore, miR-29b-3p inhibition alleviated inflammatory cells infiltration and pro-inflammatory cytokines secretion in the lung of PM-exposed mice. These findings firstly revealed that miR-29b-3p acted as a novel modulator of PM-induced inflammatory responses by targeting the C1QTNF6/AMPK signaling pathway, which contributes to a better understanding of the biological mechanisms underlying adverse PM-induced respiratory health effects.

Desmoplasia in the extracellular matrix (ECM) is one of the hallmarks of pancreatic cancer (PC), a virtually incurable disease. Decorin, a classical small leucine-rich proteoglycan found in the ECM, was upregulated in PC tissue samples according to the data of TCGA. However, decorin plays a protective role in the ECM. So it is necessary to study the roles of decorin in the progression of PC. A significantly upregulated expression of decorin was observed in the PC tissue samples compared with the normal tissues. However, there was no considerable difference in the level of expression of decorin during different pathological stages, which was supported by the immunoblot analysis. Western blot showed a higher expression of decorin A in the para-carcinoma tissue than in the cancerous tissue but the expression of decorin B, C, and D was elevated in the cancerous tissue. The results of the MTT and scratch wound healing assays revealed an elevated proliferation ability and migration rate in decorin B-overexpressing cells but were inhibited in the decorin A-overexpressing cells. Overexpression of decorin A significantly elevated the expression of the apoptosis-related genes and Decorin B-overexpression elevated proliferation-related genes. All the results showed that decorin B played important roles in the promoting of PC.

We investigated the association between single nucleotide polymorphisms (SNPs) in the HIF1A gene and the prognosis of advanced non-small cell lung cancer (NSCLC) patients undergoing radiation therapy. Patient overall survival (OS) and progression-free survival (PFS) were analyzed. The rs11549465 TT genotype was associated with poor PFS (P<0.001) and OS (P=0.001). The rs2057482 TT genotype was also associated with poor PFS (P=0.002) and OS (P=0.007). Stratified analyses revealed that these associations occurred in patients with a smoking history, squamous cell carcinoma, and stage IIIA disease, as well as those receiving radiation therapy a radiation dose of ≥70 Gy. We found associations between SNPs and PFS but not OS in patients without a smoking history, other histological types, and stage IIIB disease, as well as those undergoing chemoradiotherapy with a radiation dose of <70 Gy. No associations were observed between rs11549467 or rs110873142 and NSCLC prognosis. These results suggest that HIF1A polymorphisms can be used as independent prognostic biomarkers for NSCLC patients receiving radiation therapy.

Treacle ribosome biogenesis factor 1 (TCOF1) plays a crucial role in multiple processes, including ribosome biogenesis, DNA damage response (DDR), mitotic regulation, and telomere integrity. However, its role in cancers remains unclear. We aimed to visualize the expression, prognostic, and mutational landscapes of TCOF1 across cancers and to explore its association with immune infiltration. In this work, we integrated information from TCGA and GEO to explore the differential expression and prognostic value of TCOF1. Then, the mutational profiles of TCOF1 in cancers were investigated. We further determined the correlation between TCOF1 and immune cell infiltration levels. Additionally, we determined correlations among certain immune checkpoints, microsatellite instability, tumor mutational burden (TMB), and TCOF1. Potential pathways of TCOF1 in tumorigenesis were analyzed as well. In general, tumor tissue had a higher expression level of TCOF1 than normal tissue. The prognostic value of TCOF1 was multifaceted, depending on type of cancer. TCOF1 was correlated with tumor purity, CD8+ T cells, CD4+ T cells, B cells, neutrophils, macrophages, and dendritic cells (DCs) in 6, 14, 16, 12, 20, 13, and 17 cancer types, respectively. TCOF1 might act on ATPase activity, microtubule binding, tubulin binding, and catalytic activity (on DNA), and participate in tumorigenesis through "cell cycle" and "cellular-senescence" pathways. TCOF1 could affect pan-cancer prognosis and was correlated with immune cell infiltration. "Cell cycle" and "cellular-senescence" pathways were involved in the functional mechanisms of TCOF1, a finding that awaits further experimental validation.

Exosomes are messengers for intercellular communication and signal transduction. Circular RNA (circRNA) abnormal expression and regulation are involved in the occurrence and development of a variety of tumors. In the present study, exosomes in the serum of five patients with non-small cell lung cancer (NSCLC) were isolated before and after EGFR-TKIs resistance, and the circRNA expression profile was screened using a circRNA microarray. The effects of the exosome circRNA_102481 on cell proliferation and apoptosis were analyzed. The interaction between miR-30a-5p and circRNA_102481 or ROR1 was predicted by starBase software, and was confirmed by RNA pull-down and dual-luciferase reporter assays. The results showed that exosomes containing circRNA_102481 were significantly up-regulated in NSCLC with EGFR-TKIs resistance (p<0.05), and that circRNA_102481 was mainly secreted by EGFR-TKIs resistance cell via exosomes (p<0.05). Both circRNA_102481 silencing and si-circRNA_102481 transported by exosomes could inhibit EGFR-TKIs resistance cell proliferation and promote cell apoptosis and circRNA_102481 overexpression could promote EGFR-TKIs sensitive cell proliferation and inhibit cell apoptosis in vitro (p<0.05). CircRNA_102481 served as a miR-30a-5p sponge to regulate ROR1 expression (p<0.05). Furthermore, the expression of circRNA_102481 in exosomes was associated with TNM stage, tumor differentiation status, brain metastasis, and PFS and OS duration. Therefore, it was concluded that tumor-derived exosomal circRNA_ 102481 could contribute to EGFR-TKIs resistance via the microRNA-30a-5p/ROR1 axis in NSCLC. Exosomal circRNA_102481 may serve as a novel diagnostic biomarker and a therapeutic target for EGFR-TKIs resistance in NSCLC.

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

Elderly patients are prone to cognitive impairment and memory loss after surgical operations. This perioperative cerebral damage, named postoperative cognitive dysfunction (POCD), is profoundly affected by anesthesia. N6-methyladenosine (m6A) RNA methylation is a widely-studied epigenetic modification to regulate gene expression; however, is has never been studied in POCD. In the present study, elderly POCD mouse models were constructed using sevoflurane, and we observed a compromised global m6A RNA methylation in the mice's hippocampuses compared with the control. Our RIP-Seq data suggested that 1244 genes (SOX2, SYN1, and BDNF) showed m6A RNA methylation in their 5'UTRs, which was significantly lower than that in the control; while only 56 genes (BACE1 and IL17A) showed m6A RNA methylation in their 5'UTRs, which was significantly higher than that in the control. Unexpectedly, m6A RNA methylation with significant differences in exons, introns, or 3'UTRs was observed in only few genes. Although we failed to find any differences in the expression of m6A-associated proteins, such as m6A "writers", "erasers", and "readers", between the sevoflurane treatment and control groups, RIP-qPCR assays indicated that the binding affinity of METTL3 on mRNA 5'UTRs was particularly weakened in target genes by sevoflurane. Finally, we found that phosphorylation of METTL3 could be reduced by sevoflurane because of the inactivation of the MAPK/ERK pathway. Overall, our study determined that the inactivation of METTL3 in the mouse hippocampus, induced by sevoflurane-mediated MAPK/ERK suppression in vivo, resulted in a perturbation in m6A RNA methylation signals in the pathogenesis of POCD.

Mounting evidence has shown that miRNA-150 expression is upregulated in gastric cancer (GC) and is associated with gastric carcinogenesis, but the underlying oncogenic mechanism remains elusive. Here, we discovered that miRNA-150 targets the tumor suppressor SUFU to promote cell proliferation, migration, and the epithelial-mesenchymal transition (EMT) via the dual activation of Hedgehog (Hh) and Wnt signaling. MiRNA-150 was highly expressed in GC tissues and cell lines, and the level of this miRNA was negatively related to that of SUFU. In addition, both the miRNA-150 and SUFU levels were associated with tumor differentiation. Furthermore, miRNA-150 activated GC cell proliferation and migration in vitro. We found that miRNA-150 inhibitors repressed not only Wnt signaling by promoting cytoplasmic β-catenin localization, but also repressed Hh signaling and EMT. MiRNA-150 inhibition also resulted in significant tumor volume reductions in vivo, suggesting the potential application of miRNA-150 inhibitors in GC therapy. The expression of genes downstream of Hh and Wnt signaling was also reduced in tumors treated with miRNA-150 inhibitors. Notably, anti-SUFU siRNAs rescued the inhibitory effects of miRNA-150 inhibitors on Wnt signaling, Hh activation, EMT, cell proliferation, cell migration, and colony formation. Taken together, these findings indicate that miRNA-150 is oncogenic and promotes GC cell proliferation, migration, and EMT by activating Wnt and Hh signaling via the suppression of SUFU expression.

Familial longevity is characterized by beneficial metabolic phenotype in lipid metabolism and APOE genetic variation. Although effects of lipid metabolism and the genetic basis for human longevity remain largely unclear, the contribution of high-density lipoprotein cholesterol (HDL-C) and APOE ε2 allele has been repeatedly demonstrated. This study was designed to determine whether ApoE isoforms and HDL-C levels marked the familial longevity status in an offspring cohort with the age range of 20-89 years old and subsequently to explore the correlation between these two markers and the aging. In the Bama Aging Study (BAS), we recruited 312 offspring from longevity historical families and 298 controls from non-longevity historical families. Information on APOE genotype frequencies, lipid levels, and population characteristics were recorded. No evidence was found to support the association of APOE genotypes with HDL-C and age. HDL-C was significantly higher in longevity group (p < 0.0001). Scatter plot showed a moderately strong linear relationship between the HDL-C level and age in longevity group (r = 0.213, p < 0.001). We conclude that the variation of the APOE gene may not influence familial longevity status at a certain age but the moderate-high HDL-C level contributes to the familial longevity in Bama.

Copy number variations (CNVs) have been shown to cause numerous diseases, however, their roles in human lifespan remain elusive. In this study, we investigate the association of CNVs with longevity by comparing the Han Chinese genomes of long-lived individuals from 90 to 117 years of age and the middle-aged from 30 to 65. Our data demonstrate that the numbers of CNVs, especially deletions, increase significantly in a direct correlation with longevity. We identify eleven CNVs that strongly associate with longevity; four of them locate in the chromosome bands, 7p11.2, 20q13.33, 19p12 and 8p23.3 and overlap partially with the CNVs identified in long-lived Danish or U.S. populations, while the other seven have not been reported previously. These CNV regions encode nineteen known genes, and some of which have been shown to affect aging-related phenotypes such as the shortening of telomere length (ZNF208), the risk of cancer (FOXA1, LAMA5, ZNF716), and vascular and immune-related diseases (ARHGEF10, TOR2A, SH2D3C). In addition, we found several pathways enriched in long-lived genomes, including FOXA1 and FOXA transcription factor networks involved in regulating aging or age-dependent diseases such as cancer. Thus, our study has identified longevity-associated CNV regions and their affected genes and pathways. Our results suggest that the human genome structures such as CNVs might play an important role in determining a long life in human.

Nonculprit lesions are closely related to the prognosis of patients with ST-segment elevation myocardial infarction (STEMI). Our previous research found that ischemic postconditioning (IP) could inhibit the progression of nonculprit lesions. However, the mechanism by which IP regulates the occurrence and development of nonculprit lesions remains unclear.