Human embryonic stem cells (hESCs) can provide insights into development of inaccessible human tissues such as embryonic endoderm. Progress in this area has been hindered by a lack of methods for isolating endodermal cells and tracing fates of their differentiated progeny. By using homologous recombination in human ESCs, we inserted an enhanced green fluorescent protein (eGFP) transgene into the SOX17 locus, a postulated marker of human endoderm. FACS purification and gene expression profiling confirmed that SOX17(+)-hESC progeny expressed endodermal markers and unveiled specific cell surface protein combinations that permitted FACS-based isolation of primitive gut tube endodermal cells produced from unmodified human ESCs and from induced pluripotent stem cells (iPSC). Differentiating SOX17(+) endodermal cells expressed markers of liver, pancreas, and intestinal epithelium in vitro and gave rise to endodermal progeny in vivo. Thus, prospective isolation, lineage tracing, and developmental studies of SOX17(+) hESC progeny have revealed fundamental aspects of human endodermal biology.

Small nucleolar RNA host gene 12 (SNHG12), as one of the long non-coding RNAs (lncRNAs), plays an oncogenic role in various cancers, however, its role in the chemoresistance of non-small cell lung cancer (NSCLC) is unclear. In this study, we investigated the effect of SNHG12 on multidrug resistance (MDR) in NSCLC. The results showed that SNHG12 was high-expressed and miR-181a was low-expressed in NSCLC tumor tissues and cell lines. Knockdown of SNHG12 reversed the resistance to cisplatin, paclitaxel and gefitinib in A549/DDP, A549/PTX and PC9/AB2 cells through inducing cell apoptosis. Moreover, SNHG12 silencing suppressed MAPK1 and MAP2K1 expression by upregulating miR-181a, leading to inhibition of the MAPK/Slug pathway through decreasing phosphorylated MAPK1 (p-MAPK1), phosphorylated MAP2K1 (p-MAP2K1) and Slug levels. Furthermore, downregulation of SNHG12 enhanced the sensitivity of NSCLC cells to cisplatin in nude mice. Overall, our study is the first to identify a SNHG12-miR-181a-MAPK/Slug axis to elucidate in part how SNHG12 exert functions in NSCLC MDR, providing a novel therapeutic target to overcome MDR in NSCLC.

Transition of acute kidney injury (AKI) to chronic kidney disease (CKD) represents an important cause of kidney failure. However, how AKI is transformed into CKD remains elusive. Following folic acid injury, mice developed AKI with ensuing CKD transition, featured by variable degrees of interstitial fibrosis and tubular cell atrophy and growth arrest. This lingering injury of renal tubules was associated with sustained oxidative stress that was concomitant with an impaired Nrf2 antioxidant defense, marked by mitigated Nrf2 nuclear accumulation and blunted induction of its target antioxidant enzymes, like heme oxygenase (HO)-1. Activation of the canonical Keap1/Nrf2 signaling, nevertheless, seems intact during CKD transition because Nrf2 in injured tubules remained activated and elevated in cytoplasm. Moreover, oxidative thiol modification and activation of Keap1, the cytoplasmic repressor of Nrf2, was barely associated with CKD transition. In contrast, glycogen synthase kinase (GSK)3β, a key modulator of the Keap1-independent Nrf2 regulation, was persistently overexpressed and hyperactive in injured tubules. Likewise, in patients who developed CKD following AKI due to diverse etiologies, like volume depletion and exposure to radiocontrast agents or aristolochic acid, sustained GSK3β overexpression was evident in renal tubules and coincided with oxidative damages, impaired Nrf2 nuclear accumulation and mitigated induction of antioxidant gene expression. Mechanistically, the Nrf2 response against oxidative insult was sabotaged in renal tubular cells expressing a constitutively active mutant of GSK3β, but reinforced by ectopic expression of dominant negative GSK3β in a Keap1-independent manner. In vivo in folic acid-injured mice, targeting GSK3β in renal tubules via conditional knockout or by weekly microdose lithium treatment reinstated Nrf2 antioxidant response in the kidney and hindered AKI to CKD transition. Ergo, our findings suggest that GSK3β-mediated Keap1-independent regulation of Nrf2 may serve as an actionable therapeutic target for modifying the long-term sequelae of AKI.

Identification of important nodes in complex networks has attracted an increasing attention over the last decade. Various measures have been proposed to characterize the importance of nodes in complex networks, such as the degree, betweenness and PageRank. Different measures consider different aspects of complex networks. Although there are numerous results reported on undirected complex networks, few results have been reported on directed biological networks. Based on network motifs and principal component analysis (PCA), this paper aims at introducing a new measure to characterize node importance in directed biological networks. Investigations on five real-world biological networks indicate that the proposed method can robustly identify actually important nodes in different networks, such as finding command interneurons, global regulators and non-hub but evolutionary conserved actually important nodes in biological networks. Receiver Operating Characteristic (ROC) curves for the five networks indicate remarkable prediction accuracy of the proposed measure. The proposed index provides an alternative complex network metric. Potential implications of the related investigations include identifying network control and regulation targets, biological networks modeling and analysis, as well as networked medicine.