Molecular and biochemical investigations of the anti-fatigue effects of tea polyphenols and fruit extracts of Lycium ruthenicum Murr. on mice with exercise-induced fatigue

Background: The molecular mechanisms regulating the therapeutic effects of plant-based ingredients on the exercise-induced fatigue (EIF) remain unclear. The therapeutic effects of both tea polyphenols (TP) and fruit extracts of Lycium ruthenicum (LR) on mouse model of EIF were investigated.Methods: The variations in the fatigue-related biochemical factors, i.e., lactate dehydrogenase (LDH), superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-2 (IL-2), and interleukin-6 (IL-6), in mouse models of EIF treated with TP and LR were determined. The microRNAs involved in the therapeutic effects of TP and LR on the treatment of mice with EIF were identified using the next-generation sequencing technology.Results: Our results revealed that both TP and LR showed evident anti-inflammatory effect and reduced oxidative stress. In comparison with the control groups, the contents of LDH, TNF-α, IL-6, IL-1β, and IL-2 were significantly decreased and the contents of SOD were significantly increased in the experimental groups treated with either TP or LR. A total of 23 microRNAs (21 upregulated and 2 downregulated) identified for the first time by the high-throughput RNA sequencing were involved in the molecular response to EIF in mice treated with TP and LR. The regulatory functions of these microRNAs in the pathogenesis of EIF in mice were further explored based on Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses with a total of over 20,000–30,000 target genes annotated and 44 metabolic pathways enriched in the experimental groups based on GO and KEGG databases, respectively.Conclusion: Our study revealed the therapeutic effects of TP and LR and identified the microRNAs involved in the molecular mechanisms regulating the EIF in mice, providing strong experimental evidence to support further agricultural development of LR as well as the investigations and applications of TP and LR in the treatment of EIF in humans, including the professional athletes

Integrative analysis identifies an immune-relevant epigenetic signature for prognostication of non-G-CIMP glioblastomas

National audienceThe clinical and molecular implications of DNA methylation alterations remain unclear among the majority of glioblastomas (GBMs) without glioma-CpGs island methylator phenotype (G-CIMP); integrative multi-level molecular profiling may provide useful information. Independent cohorts of non-G-CIMP GBMs or IDH wild type (wt) lower-grade gliomas (LGGs) from local and public databases with DNA methylation and gene expression microarray data were included for discovery and validation of a multimarker signature, combined using a RISK score model. Bioinformatic and in vitro functional analyses were employed for biological validation. Using a strict multistep selection approach, we identified eight CpGs, each of which was significantly correlated with overall survival (OS) of non-G-CIMP GBMs, independent of age, the O-6-methylguanine-DNA methyltransferase (MGMT) methylation status, treatments and other identified CpGs. An epigenetic RISK signature of the 8 CpGs was developed and validated to robustly and independently prognosticate prognosis in different cohorts of not only non-G-GIMP GBMs, but also IDHwt LGGs. It also showed good discriminating value in stratified cohorts by current clinical and molecular factors. Bioinformatic analysis revealed consistent correlation of the epigenetic signature to distinct immune-relevant transcriptional profiles of GBM bulks. Functional experiments showed that S100A2 appeared to be epigenetically regulated by one identified CpG and was associated with GBM cell proliferation, apoptosis, invasion, migration and immunosuppression. The prognostic 8-CpGs RISK score signature may be of promising value for refining current glioma risk classification, and its potential links to distinct immune phenotypes make it a promising biomarker candidate for predicting response to anti-glioma immunotherapy

Chemopreventive Role of Apigenin against the Synergistic Carcinogenesis of Human Papillomavirus and 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone

Tobacco smoke and human papillomavirus (HPV) are both crucial causes of cancer, and their cooperative carcinogenesis has drawn more attention in recent years. Apigenin (AP), a typical flavonoid abundantly found in flowers of plants, vegetables, and fruits, has been demonstrated to exert an anti-carcinogenic effect on various types of cancer. In this study, we investigated the capability of AP against malignant transformation and DNA damage of immortalized human esophageal epithelial (SHEE) cells induced by the synergism of HPV18 and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The results indicated that the enhancement of migration, invasion, and proliferation ability of SHEE cells induced by HPV and NNK could be effectively inhibited by AP. Moreover, the levels of pyridyloxybutylated (POB)-DNA adducts induced by NNK via P450-catalyzed metabolic activation could also be significantly suppressed by AP. Further analyses on the molecular mechanism revealed that AP inhibited the synergistic carcinogenesis of NNK and HPV on SHEE cells by reducing the expression of mutp53, CDK4, Cyclin D1, and p-Rb (Ser 780), increasing caspase-3 activity, thereby arresting the cell cycle at G1 phase and promoting apoptosis of SHEE cells. We hypothesize that the decrease in NNK-induced POB-DNA adduct levels is related to the deactivation of P450 by AP, which needs to be confirmed in future studies. This study highlights that AP may be employed as a promising chemopreventive agent against cancers in smokers with an HPV infection