Paternal genetic affinity between western Austronesians and Daic populations

<p>Abstract</p> <p>Background</p> <p>Austronesian is a linguistic family spread in most areas of the Southeast Asia, the Pacific Ocean, and the Indian Ocean. Based on their linguistic similarity, this linguistic family included Malayo-Polynesians and Taiwan aborigines. The linguistic similarity also led to the controversial hypothesis that Taiwan is the homeland of all the Malayo-Polynesians, a hypothesis that has been debated by ethnologists, linguists, archaeologists, and geneticists. It is well accepted that the Eastern Austronesians (Micronesians and Polynesians) derived from the Western Austronesians (Island Southeast Asians and Taiwanese), and that the Daic populations on the mainland are supposed to be the headstream of all the Austronesian populations.</p> <p>Results</p> <p>In this report, we studied 20 SNPs and 7 STRs in the non-recombining region of the 1,509 Y chromosomes from 30 China Daic populations, 23 Indonesian and Vietnam Malayo-Polynesian populations, and 11 Taiwan aboriginal populations. These three groups show many resemblances in paternal lineages. Admixture analyses demonstrated that the Daic populations are hardly influenced by Han Chinese genetically, and that they make up the largest proportion of Indonesians. Most of the population samples contain a high frequency of haplogroup O1a-M119, which is nearly absent in other ethnic families. The STR network of haplogroup O1a* illustrated that Indonesian lineages did not derive from Taiwan aborigines as linguistic studies suggest, but from Daic populations.</p> <p>Conclusion</p> <p>We show that, in contrast to the Taiwan homeland hypothesis, the Island Southeast Asians do not have a Taiwan origin based on their paternal lineages. Furthermore, we show that both Taiwan aborigines and Indonesians likely derived from the Daic populations based on their paternal lineages. These two populations seem to have evolved independently of each other. Our results indicate that a super-phylum, which includes Taiwan aborigines, Daic, and Malayo-Polynesians, is genetically educible.</p

Metformin Increases Survival in Hypopharyngeal Cancer Patients with Diabetes Mellitus: Retrospective Cohort Study and Cell-Based Analysis

Hypopharyngeal squamous cell carcinoma (HSCC) is usually diagnosed at an advanced stage, leading to a poor prognosis. Even after improvement of surgical techniques, chemotherapy, and radiation technology, the survival rate of HSCC remains poor. Metformin, which is commonly used for type 2 diabetes mellitus (DM), has been suggested to reduce the risk of various cancer types. However, only a few clinical studies mentioned the relationship between metformin use and HSCC. Hence, the aim of this study was to elucidate the specific effect and mechanism of action of metformin in hypopharyngeal cancer. We first assessed whether metformin use has an effect on hypopharyngeal cancer patients with DM by conducting a retrospective cohort study. Our results showed that DM hypopharyngeal cancer patients who used metformin exhibited significantly better overall survival rates than that without metformin treatment. The cell-based analysis further indicated that metformin treatment regulated p38/JNK pathway to reduce Cyclin D1 and Bcl-2 expressions. In addition, metformin activated the pathways of AMPKα and MEK/ERK to phosphorylate p27(Thr198) and reduce mTOR phosphorylation in cells. These actions direct cells toward G1 cell cycle arrest, apoptosis, and autophagy. Our results, through combining a clinical cohort analysis with an in vitro study, demonstrate that metformin can be used for drug repositioning in the treatment of DM patients with hypopharyngeal cancer

Interleukin-13 Inhibits Lipopolysaccharide-Induced BPIFA1 Expression in Nasal Epithelial Cells

<div><p>Short palate, lung, and nasal epithelium clone 1 (SPLUNC1) protein is expressed in human nasopharyngeal and respiratory epithelium and has demonstrated antimicrobial activity. SPLUNC1 is now referred to as bactericidal/permeability-increasing fold containing family A, member 1 (BPIFA1). Reduced BPIFA1 expression is associated with bacterial colonization in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Interleukin 13 (IL-13), predominately secreted by T helper 2 (T_H2) cells, has been found to contribute to airway allergies and suppress BPIFA1 expression in nasal epithelial cells. However, the molecular mechanism of IL-13 perturbation of bacterial infection and BPIFA1 expression in host airways remains unclear. In this study, we found that lipopolysaccharide (LPS)-induced BPIFA1 expression in nasal epithelial cells was mediated through the JNK/c-Jun signaling pathway and AP-1 activation. We further demonstrated that IL-13 downregulated the LPS-induced activation of phosphorylated JNK and c-Jun, followed by attenuation of BPIFA1 expression. Moreover, the immunohistochemical analysis showed that IL-13 prominently suppressed BPIFA1 expression in eosinophilic CRSwNP patients with bacterial infection. Taken together, these results suggest that IL-13 plays a critical role in attenuation of bacteria-induced BPIFA1 expression that may result in eosinophilic CRSwNP.</p></div

Inhibition of c-Jun suppresses LPS-induced BPIFA1 expression.

<p>Cells were pretreated with 10 μM of SP600125, curcumin, or tanshinone (inhibitors of c-Jun) for 30 min, followed by incubation with LPS (10 μg/ml) for 2 h. Cells were washed and treated with antibodies against (A) phosphorylated c-Jun or (B) BPIFA1, followed by incubation with FITC–conjugated anti-mouse IgG (green). Cells were probed with DAPI to visualize the nucleus (blue) and analyzed by confocal fluorescence microscopy. Bars, 10 μm.</p

IL-13-mediates attenuation of LPS-induced BPIFA1 expression.

<p>RPMI-2650 cells, either treated or untreated with IL-13 (10 ng/ml) for 48 h, were incubated with or without LPS (10 μg/ml) for further 2 h. Cell lysates were prepared to analyze the protein expression levels by using western blot. β-actin was used as the loading control. The western blots were carried out independently in triplicate and results were representative of one of three independent experiments. The expression level of each protein was quantified by signal intensity and was indicated at the bottom of each lane. The quantitative analysis of western blot for three independent experiments was shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0143484#pone.0143484.s004" target="_blank">S4 Fig</a>. ANOVA with Tukey’s test was used to compare the overall difference between the groups. <i>P</i> < 0.05 was considered statistically significant.</p

LPS induces BPIFA1 expression in nasal epithelial cells.

<p>(A) RPMI-2650 cells were treated with various concentrations (0–20 μg/ml) of LPS for 2 h, and mRNA levels of BPIFA1 were analyzed by quantitative real-time PCR. (B) Cell lysates were then prepared to measure BPIFA1 protein expression levels by western blot after incubation with LPS for 24 h. Protein expression levels of BPIFA1 were quantified by densitometric analysis and normalized to those of β-actin. ANOVA with Tukey’s test was used to compare the overall difference between the groups. *, <i>P</i> < 0.05 compared to LPS-untreated control group.</p

JNK/c-Jun pathway is involved in LPS-mediated up-regulation of BPIFA1 expression in nasal epithelial cells.

<p>(A) Cells were pretreated for 1 h with 20 μM PD98059 (ERK inhibitor), 10 μM SP600125 (JNK inhibitor), or 20 μM SB203580 (p38 inhibitor) and incubated with 10 μg/ml LPS for 2 h. (B) Cells were transfected with a JNK-dominant negative (DN-JNK) mutant for 24 h or pretreated with SP600125 for 30 min prior to incubation with LPS for 1 h. The protein expression levels were determined using western blot. β-actin was used as the loading control. The western blots were carried out independently in triplicate and results were representative of one of three independent experiments. The expression level of each protein was quantified by signal intensity and was indicated at the bottom of each lane. The quantitative analysis of western blot for three independent experiments was shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0143484#pone.0143484.s002" target="_blank">S2 Fig</a>. ANOVA with Tukey’s test was used to compare the overall difference between the groups. <i>P</i> < 0.05 was considered statistically significant.</p

Bacterial infection is associated with elevated IL-13 secretion and reduced BPIFA1 expression in sinonasal tissues.

<p>Representative immunohistochemical staining of BPIFA1 (upper panel) and IL-13 (lower panel) expressions in eosinophilic CRSwNP patients (A) without or (B, C) with bacterial infection. Arrows indicated the expression of IL-13 in the bacterial infection tissue (C). The images were photographed at a magnification of 200×.</p

Model depicting IL-13 inhibition of LPS-induced BPIFA1 expression in nasal epithelial cells.

<p>(A) The bacterial cell wall component LPS upregulates BPIFA1 expression through the JNK/c-Jun signaling pathway, followed by AP-1 activation. (B) IL-13, a T_H2-skewed cytokine, suppresses LPS-induced BPIFA1 expression in nasal epithelial cells from patients with eosinophilic CRSwNP.</p