Age-dependent immune profile in healthy individuals: an original study, systematic review and meta-analysis

Background: The circulatory peripheral immune system is the most convenient approach for determining an individual’s immune status. Due to various reasons, while previous studies have addressed the critical impact of age, most individual studies did not analyze immunosenescence in a systemic manner, which complicates the possibility of building a reference range for age-dependent immune profiles for effective immune monitoring. To address this gap, this study analyzed a group of healthy individuals to establish age-specific reference ranges of the healthy circulatory immune profile, and a systematic review and meta-analysis were conducted to validate the findings and create generalizable immune cell reference ranges. Results: Our study recruited a total of 363 healthy Taiwanese adults (median age 42 years [IQR 30, 62], age range 21 to 87 years, 43.3% male), including 158 under 40 years old, 127 between 40–64 years old, and 78 over 64 years old. Significant age-related alterations were observed in both adaptive and innate immune cell subsets. CD8 + T cells decreased and CD4/CD8 ratio increased, with notable increases in NK cells. CD4 + T cells were less impacted by aging, while CD8 + T cells significantly lost CD28 and increased CD31 expression with age. A clear reverse trend in naïve and memory subsets of CD4 + and CD8 + T cells was observed. Detailed reference ranges for immune cell subsets in healthy Taiwanese adults were established. A systematic review included 7,425 adults and a meta-analysis of 12 eligible studies confirmed our findings in Taiwan, enhancing generalizability. Conclusions: Combined with previous studies and original data through a systematic review and meta-analysis, we highlighted and quantified significant immune profile differences between older and younger individuals. The sex and age-specific reference ranges for peripheral immune cell subsets can serve as a basis for effective immune monitoring of various aging-related illnesses

Chronic Unpredictable Mild Stress Promotes Atherosclerosis via HMGB1/TLR4-Mediated Downregulation of PPARγ/LXRα/ABCA1 in ApoE-/- Mice

Background: Although our previous studies have confirmed that the activation of TLR4 is implicated in the development of atherosclerosis induced by chronic unpredicted mild stress (CUMS), the underling mechanism is largely unclear. Here, we hypothesized that CUMS accelerates atherosclerotic development through lowering PPARγ/LXRα-ABCA1 expression via HMGB1/TLR4 signaling.Methods: In present study, CUMS atherosclerotic animal models were established with AopE-/- mice, and CUMS Raw 264.7 macrophage models were mimicked by high corticosterone treatment, These models were treated with Ethyl pyruvate (EP, an inhibitor of HMGB1), TLR4 inhibitor TAK-242, and PPARγ agonist RSG (Rosiglitazone) to test our hypothesis, respectively.Results: Our results indicated that the protein levels of HMGB1, TLR4, and pro-inflammatory cytokines including IL-1β, TNF-α were elevated with the development of atherosclerosis in CUMS mice, while the expressions of PPARγ, LXRα, and ABCA1 declined. Notably, HMGB1 inhibition by EP reversed CUMS-induced atherosclerotic development, pro-inflammatory cytokines upregulation, and PPARγ/LXRα-ABCA1 downregulation. The same trend was observed in the stressed mice treatment with TAK-242. Further experimental evidences indicated that EP, TAK-242, and RSG treatment notably corrected foam cell formation, HMGB1 release, and down-regulation of LXRα and ABCA1 in CUMS Raw 264.7 macrophage model.Conclusion: These results indicate that CUMS exacerbates atherosclerosis is likely via HMGB1-mediated downregulation of PPARγ/LXRα-ABCA1 through TLR4. These data reveal a novel mechanism by which CUMS aggravates atherosclerosis and may offer a potential therapeutic target for this disease

miRTarBase update 2014: an information resource for experimentally validated miRNA-target interactions

MicroRNAs (miRNAs) are small non-coding RNA molecules capable of negatively regulating gene expression to control many cellular mechanisms. The miRTarBase database (http://mirtarbase.mbc.nctu.edu.tw/) provides the most current and comprehensive information of experimentally validated miRNA-target interactions. The database was launched in 2010 with data sources for >100 published studies in the identification of miRNA targets, molecular networks of miRNA targets and systems biology, and the current release (2013, version 4) includes significant expansions and enhancements over the initial release (2010, version 1). This article reports the current status of and recent improvements to the database, including (i) a 14-fold increase to miRNA-target interaction entries, (ii) a miRNA-target network, (iii) expression profile of miRNA and its target gene, (iv) miRNA target-associated diseases and (v) additional utilities including an upgrade reminder and an error reporting/user feedback system

Overexpression of YAP 1 contributes to progressive features and poor prognosis of human urothelial carcinoma of the bladder

BACKGROUND: Yes-associated protein 1 (YAP 1), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene in multiple tumors. However, the expression dynamics of YAP 1 in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance are unclear. METHODS: In this study, the methods of quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting and immunohistochemistry (IHC) were utilized to investigate mRNA/ protein expression of YAP 1 in UCBs. Spearman’s rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data. RESULTS: Up-regulated expression of YAP 1 mRNA and protein was observed in the majority of UCBs by qRT-PCR and Western blotting, when compared with their paired normal bladder tissues. By IHC, positive expression of YAP 1 was examined in 113/213 (53.1%) of UCBs and in 6/86 (7.0%) of normal bladder specimens tissues. Positive expression of YAP 1 was correlated with poorer differentiation, higher T classification and higher N classification (P < 0.05). In univariate survival analysis, a significant association between positive expression of YAP 1 and shortened patients’ survival was found (P < 0.001). In different subsets of UCB patients, YAP 1 expression was also a prognostic indicator in patients with grade 2 (P = 0.005) or grade 3 (P = 0.046) UCB, and in patients in pT1 (P = 0.013), pT2-4 (P = 0.002), pN- (P < 0.001) or pT2-4/pN- (P = 0.004) stage. Importantly, YAP 1 expression (P = 0.003) together with pT and pN status (P< 0.05) provided significant independent prognostic parameters in multivariate analysis. CONCLUSIONS: Our findings provide evidences that positive expression of YAP 1 in UCB may be important in the acquisition of an aggressive phenotype, and it is an independent biomarker for poor prognosis of patients with UCB

Associations of multiple visual rating scales based on structural magnetic resonance imaging with disease severity and cerebrospinal fluid biomarkers in patients with Alzheimer’s disease

The relationships between multiple visual rating scales based on structural magnetic resonance imaging (sMRI) with disease severity and cerebrospinal fluid (CSF) biomarkers in patients with Alzheimer’s disease (AD) were ambiguous. In this study, a total of 438 patients with clinically diagnosed AD were recruited. All participants underwent brain sMRI scan, and medial temporal lobe atrophy (MTA), posterior atrophy (PA), global cerebral atrophy-frontal sub-scale (GCA-F), and Fazekas rating scores were visually evaluated. Meanwhile, disease severity was assessed by neuropsychological tests such as the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Clinical Dementia Rating (CDR). Among them, 95 patients were tested for CSF core biomarkers, including Aβ1–42, Aβ1–40, Aβ1–42/Aβ1–40, p-tau, and t-tau. As a result, the GCA-F and Fazekas scales showed positively significant correlations with onset age (r = 0.181, p &lt; 0.001; r = 0.411, p &lt; 0.001, respectively). Patients with late-onset AD (LOAD) showed higher GCA-F and Fazekas scores (p &lt; 0.001, p &lt; 0.001). With regard to the disease duration, the MTA and GCA-F were positively correlated (r = 0.137, p &lt; 0.05; r = 0.106, p &lt; 0.05, respectively). In terms of disease severity, a positively significant association emerged between disease severity and the MTA, PA GCA-F, and Fazekas scores (p &lt; 0.001, p &lt; 0.001, p &lt; 0.001, p &lt; 0.05, respectively). Moreover, after adjusting for age, gender, and APOE alleles, the MTA scale contributed to moderate to severe AD in statistical significance independently by multivariate logistic regression analysis (p &lt; 0.05). The model combining visual rating scales, age, gender, and APOE alleles showed the best performance for the prediction of moderate to severe AD significantly (AUC = 0.712, sensitivity = 51.5%, specificity = 84.6%). In addition, we observed that the MTA and Fazekas scores were associated with a lower concentration of Aβ1–42 (p &lt; 0.031, p &lt; 0.022, respectively). In summary, we systematically analyzed the benefits of multiple visual rating scales in predicting the clinical status of AD. The visual rating scales combined with age, gender, and APOE alleles showed best performance in predicting the severity of AD. MRI biomarkers in combination with CSF biomarkers can be used in clinical practice