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The article discusses the role of apolipoprotein b mRNA editing enzyme catalytic-polypeptide-like proteins 3 (APOBEC3) enzymes in autoimmune diseases. Topics include possible involvement of hA3 enzymes in disorders, genetic variants and methylation CpG sites linking APOBEC3 enzymes to autoimmune diseases, and how integrated dissection of data on genetic, epigenetic and gene expression levels would facilitate the elucidation of the underlying mechanisms.

Schematic representation of intrinsic apoptotic pathway induced by Sinularin relied on FOXO3 in prostate cancer cells. Sinularin upregulates FOXO3 via inhibiting the activity of AKT and ERK which phosphorylate FOXO3 at Ser253 and Ser294 respectively. Phosphorylation at these sites leads to FOXO3 binding to 14-3-3 protein, FOXO3 translocation to cytoplasm from nucleus, and subsequent ubiquitin–proteasome degradation. The upregulated FOXO3 increased its target PUMA, a pro-apoptotic protein belonging to the BH3 sub-family of Bcl-2 family. PUMA binds and antagonizes Bcl-2, then leads to mitochondrial outer membrane permeabilization and mitochondrial membrane potential collapses, promoting cytochrome c release and apoptosis. [Display omitted] Sinularin, a natural product that purified from soft coral, exhibits anti-tumor effects against various human cancers. However, the mechanisms are not well understood. In this study, we demonstrated that Sinularin inhibited the viability of human prostate cancer cells in a dose-dependent manner and displayed significant cytotoxicity only at high concentration against normal prostate epithelial cell RWPE-1. Flow cytometry assay demonstrated that Sinularin induced tumor cell apoptosis. Further investigations revealed that Sinularin exerted anti-tumor activity through intrinsic apoptotic pathway along with up-regulation of pro-apoptotic protein Bax and PUMA, inhibition of anti-apoptotic protein Bcl-2, mitochondrial membrane potential collapses, and release of mitochondrial proteins. Furthermore, we illustrated that Sinularin induced cell apoptosis via up-regulating PUMA through inhibition of FOXO3 degradation by the ubiquitin–proteasome pathway. To explore how Sinularin suppress FOXO3 ubiquitin–proteasome degradation, we tested two important protein kinases AKT and ERK that regulate FOXO3 stabilization. The results revealed that Sinularin stabilized and up-regulated FOXO3 via inhibition of AKT- and ERK1/2-mediated FOXO3 phosphorylation and subsequent ubiquitin–proteasome degradation. Our findings illustrated the potential mechanisms by which Sinularin induced cell apoptosis and Sinularin may be applied as a therapeutic agent for human prostate cancer. [ABSTRACT FROM AUTHOR]

It is unclear how telomere-binding protein TPP1 interacts with human telomerase reverse transcriptase (hTERT) and influences cervical cancer development and progression. This study included all eligible 156 cervical cancers diagnosed during 2003–2008 and followed up through 2014, 102 cervical intraepithelial neoplasia (CIN) patients, and 16 participants with normal cervix identified at the same period. Correlation of expression of TPP1 and hTERT in these lesions was assessed using Kappa statistics. TPP1 was knocked down by siRNA in three cervical cancer cell lines. We assessed mRNA expression using quantitative real-time polymerase chain reaction and protein expression using tissue microarray-based immunohistochemical staining. We further analyzed the impact of TPP1 expression on the overall survival of cervical cancer patients by calculating the hazard ratio (HR) with 95% confidence intervals (CIs) using the multivariable-adjusted Cox regression model. Compared to the normal cervix, high TPP1expression was significantly associated with CIN 3 and cervical cancers (P<0.001 for both). Expressions of TPP1 and hTERT were highly correlated in CIN 3 (Kappa statistics = 0.50, P = 0.005), squamous cell carcinoma (Kappa statistics = 0.22, P = 0.011), and adenocarcinoma/adenosquamous carcinoma (Kappa statistics = 0.77, P = 0.001). Mechanistically, knockdown of TPP1 inhibited the expression of hTERT in both mRNA and protein levels. High expression of TPP1 (HR = 2.61, 95% CI 1.23–5.51) and co-high expression of TPP1 and hTERT (HR = 2.38, 95% CI 1.28–4.43) were independently associated with worse survival in cervical cancer patients. TPP1 and hTERT expression was correlated and high expression of TPP1 was associated with high risk of CIN 3 and cervical cancer and could predict a worse survival in cervical cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] • Characterizing the heterogeneity of individual cognitive aging from a mitochondrial perspective. • Comprehensively assessing brain resilience through genetic metrics. • Individuals' levels of brain resilience were comprehensively measured by eight pathological characteristics. • The performance of PRS models could be efficiently improved by incorporating mitochondria-related loci. • Significant implications for the prevention and intervention of Alzheimer's disease. Identification of high-risk people for Alzheimer's disease (AD) is critical for prognosis and early management. Longitudinal epidemiologic studies have observed heterogeneity in the brain and cognitive aging. Brain resilience was described as above-expected cognitive function. The "resilience" framework has been shown to correlate with individual characteristics such as genetic factors and age. Besides, accumulative evidence has confirmed the association of mitochondria with the pathogenesis of AD. However, it is challenging to assess resilience through genetic metrics, in particular incorporating mitochondria-associated loci. In this paper, we first demonstrated that polygenic risk scores (PRS) could characterize individuals' resilience levels. Then, we indicated that mitochondria-associated loci could improve the performance of PRSs, providing more reliable measurements for the prevention and diagnosis of AD. The discovery (N = 1,550) and independent validation samples (N = 2,090) were used to construct nine types of PRSs containing mitochondria-related loci (PRSMT) from both biological and statistical aspects and combined them with known AD risk loci derived from genome-wide association studies (GWAS). Individuals' levels of brain resilience were comprehensively measured by linear regression models using eight pathological characteristics. It was found that PRSs could characterize brain resilience levels (e.g., Pearson correlation test P min = 7.96 × 10 - 9 ). Moreover, the performance of PRS models could be efficiently improved by incorporating a small number of mitochondria-related loci (e.g., Pearson correlation test P improved from 1.41 × 10 - 3 to 6.09 × 10 - 6 ). PRSs' ability to characterize brain resilience was validated. More importantly, by incorporating some mitochondria-related loci, the performance of PRSs in measuring brain resilience could be significantly improved. Our findings imply that mitochondria may play an important role in brain resilience, and targeting mitochondria may open a new door to AD prevention and therapy. [ABSTRACT FROM AUTHOR]