Utilizing the whole genomic variation of complex traits to predict the yet-to-be observed phenotypes or unobserved genetic values via whole genome prediction (WGP) and to infer the underlying genetic architecture via genome wide association study (GWAS) is an interesting and fast developing area in the context of human disease studies as well as in animal and plant breeding. Though thousands of significant loci for several species were detected via GWAS in the past decade, they were not used directly to improve WGP due to lack of proper models. Here, we propose a generalized way of building trait-specific genomic relationship matrices which can exploit GWAS results in WGP via a best linear unbiased prediction (BLUP) model for which we suggest the name BLUP|GA. Results from two illustrative examples show that using already existing GWAS results from public databases in BLUP|GA improved the accuracy of WGP for two out of the three model traits in a dairy cattle data set, and for nine out of the 11 traits in a rice diversity data set, compared to the reference methods GBLUP and BayesB. While BLUP|GA outperforms BayesB, its required computing time is comparable to GBLUP. Further simulation results suggest that accounting for publicly available GWAS results is potentially more useful for WGP utilizing smaller data sets and/or traits of low heritability, depending on the genetic architecture of the trait under consideration. To our knowledge, this is the first study incorporating public GWAS results formally into the standard GBLUP model and we think that the BLUP|GA approach deserves further investigations in animal breeding, plant breeding as well as human genetics.

Gut-derived bacterial lipopolysaccharide (LPS) and subsequent hepatic toll-like receptor 4 (TLR4) activation have been recognized to be involved in the onset of diet-induced nonalcoholic fatty liver disease (NAFLD), but little is known about the variation of LPS and TLR4 during the progression of NAFLD. Probiotics were able to inhibit proliferation of harmful bacteria and improve gastrointestinal barrier function. However, it’s unclear whether LPS/TLR4 is involved in the protection effect of probiotics on NAFLD. In this study, we described characteristic of gut microbiota structure in the progression of NAFLD, and we also analyzed the relationship between gut microbiota and LPS/TLR4 in this process. Furthermore, we applied probiotics intervention to investigate the effect of probiotics on gut flora structure, intestinal integrity, serum LPS, liver TLR4 and liver pathology. Our results showed that serum LPS and liver TLR4 were highly increased during progression of NAFLD, with gut flora diversity and gut mircobiological colonization resistance (B/E) declining. Furthermore, probiotics could improve gut microbiota structure and liver pathology. Probiotics could also downregulate serum LPS and liver TLR4. Our results suggested that both gut flora alteration and endotoxemia may be involved in the progression of NAFLD. Probiotics may delay the progression of NAFLD via LPS/TLR4 signaling.

Autophagy inhibition has been widely accepted as a promising therapeutic strategy in cancer, while the lack of effective and specific autophagy inhibitors hinders its application. Here we found that liensinine, a major isoquinoline alkaloid, inhibits late-stage autophagy/mitophagy through blocking autophagosome-lysosome fusion. This effect is likely achieved via inhibiting the recruitment of RAB7A to lysosomes but not to autophagosomes. We further investigated the effects of autophagy inhibition by liensinine on the therapeutic efficacy of chemotherapeutic drugs and found that cotreatment of liensinine markedly decreased the viability and increased apoptosis in breast cancer cells treated with various chemotherapeutic agents. Mechanistically, we found that inhibition of autophagy/mitophagy by liensinine enhanced doxorubicin-mediated apoptosis by triggering mitochondrial fission, which resulted from dephosphorylation and mitochondrial translocation of DNM1L. However, blocking autophagosome/mitophagosome formation by pharmacological or genetic approaches markedly attenuated mitochondrial fission and apoptosis in cells with combinatatorial treatment. Moreover, liensinine was synergized with doxorubicin to inhibit tumor growth in MDA-MB-231 xenograft in vivo. Our findings suggest that liensinine could potentially be further developed as a novel autophagy/mitophagy inhibitor, and a combination of liensinine with classical chemotherapeutic drugs could represent a novel therapeutic strategy for treatment of breast cancer.

Anticancer activities of flavonoids derived from Tephroseris kirilowii (Turcz.) Holub. were evaluated in human cancer cells. We isolated and identified, for the first time, eight flavonoids from T. kirilowii and found that three of them (IH: isorhamnetin, GN: genkwanin, and Aca: acacetin) inhibited cell proliferation in a variety of human cancer cell lines. These active flavonoids caused cell cycle arrest at G2/M phase and induced apoptosis and autophagy in human breast cancer cells. Molecular docking revealed that these flavonoids dock in the ATP binding pocket of PI3Kγ. Importantly, treatment with these flavonoids decreased the levels of PI3Kγ-p110, phospho-PI3K, phospho-AKT, phospho-mTOR, phospho-p70S6K, and phospho-ULK. Pretreatment with PI3Kγ specific inhibitor AS605240 potentiated flavonoids-mediated inactivation of AKT, mTOR, p70S6K, ULK, and apoptosis. Taken together, these findings represent a novel mechanism by which downregulation of PI3Kγ-p110 and consequent interruption of PI3K/AKT/mTOR/p70S6K/ULK signaling pathway might play a critical functional role in these flavonoids-induced cell cycle arrest at G2/M phase, apoptosis, and autophagy. Our studies provide novel insights into the anticancer activities of selected flavonoids and their potential uses in anticancer therapy.

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