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1.  A three-dimensional study of alveologenesis in mouse lung 
Developmental biology  2015;409(2):429-441.
Alveologenesis is the final step of lung maturation, which subdivides the alveolar region of the lung into smaller units called alveoli. Each of the nascent dividers serves as a new gas-exchange surface, and collectively they drastically increase the surface area for breathing. Disruption of alveologenesis results in simplification of alveoli, as is seen in premature infants diagnosed with bronchopulmonary dysplasia (BPD), a prevalent lung disease that is often associated with lifelong breathing deficiencies. To date, a majority of studies of alveologenesis rely on two-dimensional (2D) analysis of tissue sections. Given that an overarching theme of alveologenesis is thinning and extension of the epithelium and mesenchyme to facilitate gas exchange, often only a small portion of a cell or a cellular structure is represented in a single 2D plane. Here, we use a three-dimensional (3D) approach to examine the structural architecture and cellular composition of myofibroblasts, alveolar type 2 cells, elastin and lipid droplets in normal as well as BPD-like mouse lung. We found that 2D finger-like septal crests, commonly used to depict growing alveolar septae, are often artifacts of sectioning through fully established alveolar walls. Instead, a more accurate representation of growing septae are 3D ridges that are lined by platelet-derived growth factor receptor alpha (PDGFRA) and alpha smooth muscle actin (α-SMA)-expressing myofibroblasts, as well as the elastin fibers that they produce. Accordingly in 3D, both α-SMA and elastin were each found in connected networks underlying the 3D septal ridges rather than as isolated dots at the tip of 2D septal crests. Analysis through representative stages of alveologenesis revealed unappreciated dynamic changes in these patterns. PDGFRA-expressing cells are only α-SMA-positive during the first phase of alveologenesis, but not in the second phase, suggesting that the two phases of septae formation may be driven by distinct mechanisms. Thin elastin fibers are already present in the alveolar region prior to alveologenesis, suggesting that during alveologenesis, there is not only new elastin deposition, but also extensive remodeling to transform thin and uniformly distributed fibers into thick cables that rim the nascent septae. Analysis of several genetic as well as hyperoxia-induced models of BPD revealed that the myofibroblast organization is perturbed in all, regardless of whether the origin of defect is epithelial, mesenchymal, endothelial or environmental. Finally, analysis of relative position of PDGFRA-positive cells and alveolar type 2 cells reveal that during alveologenesis, these two cell types are not always adjacent to one another. This result suggests that the niche and progenitor relationship afforded by their close juxtaposition in the adult lung may be a later acquired property. These insights revealed by 3D reconstruction of the septae set the foundation for future investigations of the mechanisms driving normal alveologenesis, as well as causes of alveolar simplification in BPD.
PMCID: PMC4843524  PMID: 26632490
Lung; Development; Mouse; Alveologenesis
2.  Germination, Physiological Responses and Gene Expression of Tall Fescue (Festuca arundinacea Schreb.) Growing under Pb and Cd 
PLoS ONE  2017;12(1):e0169495.
Cadmium (Cd) and lead (Pb) are recognized as the most toxic metal ions due to their detrimental effects not only to plants, but also to humans. The objective of this study was to investigate the effects of Cd and Pb treatments on seed germination, plant growth, and physiological response in tall fescue (Festuca arundinacea Schreb.). We employed six treatments: CK (nutrient solution as control), T1 (1000 mg L-1 Pb), T2 (50 mg L-1 Cd), T3 (150 mg L-1 Cd), T4 (1000 mg L-1 Pb+50 mg L-1 Cd), T5 (1000 mg L-1 Pb+150 mg L-1 Cd). Antagonistic and synergistic actions were observed in tall fescue under Pb and Cd combined treatments. Under low Cd, plants exhibited higher relative germination rate, germ length, VSGR, catalase (CAT) and peroxidase (POD) activities. Additionally, in the shoots, the gene expression level of Cu/Zn SOD, FeSOD, POD, GPX, translocation factors, MDA, EL, and soluble protein contents were reduced under Pb stress. Conversely, under high Cd level, there was a decline in NRT, Pb content in shoots, Pb translocation factors, CAT activity; and an increase in VSGR, Pb content in roots, gene expression level of Cu/ZnSOD and POD in tall fescue exposed to Pb2+ regimes. On the other hand, tall fescue plants treated with low Cd exhibited lower relative germination rate, germination index, germ length, NRT, Cd content in roots. On the other hand there was higher Cd content, Cd translocation factor, CAT and POD activities, and gene expression level of Cu/Zn SOD, FeSOD, POD, GPX under Pb treatment compared with single Cd2+ treatment in the shoots. However, after high Cd exposure, plants displayed lower NRT, Cd content, CAT activity, and exhibited higher Cd contents, Cd translocation factor, MDA content, gene expression level of Cu/ZnSOD and GPX with the presence of Pb2+ relative to single Cd2+ treatment. These findings lead to a conclusion that the presence of low Cd level impacted positively towards tall fescue growth under Pb stress, while high level of Cd impacted negatively. In summary, antioxidant enzymes responded to Cd and Pb interaction at an early stage of exposure, and their gene expression profiles provided more details of the activation of those systems.
PMCID: PMC5207687  PMID: 28046098
3.  Increased Incidence of Thyroid Disease in Patients with Celiac Disease: A Systematic Review and Meta-Analysis 
PLoS ONE  2016;11(12):e0168708.
The prevalence of thyroid disease is likely increased among individuals with celiac disease (CD). In addition, exposure to gluten-free treatment may be associated with a risk of thyroid disease, but this association remains controversial. A systematic review was performed to evaluate the association between thyroid disease and CD. The articles were obtained from the PubMed, Web of Science, Embase, and Chinese WanFang bibliographical databases for the period up to May 2016. The results were analysed in a meta-analysis with odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs). There were 13 articles in this meta-analysis, including 15629 CD cases and 79342 controls. Overall, the prevalence of thyroid disease in patients with CD was significantly increased compared with that in the control groups (OR 3.08, 95% CI 2.67–3.56, P<0.001). Moreover, there was no significant difference in the OR between the gluten-treated and untreated groups (OR 1.08, 95% CI 0.61–1.92, P = 0.786). The results of our meta-analysis support the hypothesis that the prevalence of thyroid disease in patients with CD is increased compared with that in controls, which suggests that CD patients should be screened for thyroid disease. The effect of gluten-free treatment on thyroid disease needs further investigation.
PMCID: PMC5193514  PMID: 28030626
4.  Sam68/KHDRBS1-dependent NF-κB activation confers radioprotection to the colon epithelium in γ-irradiated mice 
eLife  null;5:e21957.
Previously we reported that Src-associated-substrate-during-mitosis-of-68kDa (Sam68/KHDRBS1) is pivotal for DNA damage-stimulated NF-κB transactivation of anti-apoptotic genes (Fu et al., 2016). Here we show that Sam68 is critical for genotoxic stress-induced NF-κB activation in the γ-irradiated colon and animal and that Sam68-dependent NF-κB activation provides radioprotection to colon epithelium in vivo. Sam68 deletion diminishes γ-irradiation-triggered PAR synthesis and NF-κB activation in colon epithelial cells (CECs), thus hampering the expression of anti-apoptotic molecules in situ and facilitating CECs to undergo apoptosis in mice post whole-body γ-irradiation (WBIR). Sam68 knockout mice suffer more severe damage in the colon and succumb more rapidly from acute radiotoxicity than the control mice following WBIR. Our results underscore the critical role of Sam68 in orchestrating genotoxic stress-initiated NF-κB activation signaling in the colon tissue and whole animal and reveal the pathophysiological relevance of Sam68-dependent NF-κB activation in colonic cell survival and recovery from extrinsic DNA damage.
PMCID: PMC5214542  PMID: 27996939
Sam68; KHDRBS1; radiodamage; NF-κB; colon epithelium; Mouse
5.  Development of Evidence-based Recommendations: Implications for Preparing Expert Consensus Statements 
Chinese Medical Journal  2016;129(24):2998-3000.
PMCID: PMC5198536  PMID: 27958233
Clinical Practice Guidelines; Evidence-based Medicine; Expert Consensus
6.  Metformin Treatment and Homocysteine: A Systematic Review and Meta-Analysis of Randomized Controlled Trials 
Nutrients  2016;8(12):798.
The aim of this systematic review is to assess whether metformin could change the concentration of serum homocysteine (Hcy) with and without simultaneous supplementation of B-group vitamins or folic acid. A literature search was conducted in PubMed, EmBase, and Cochrane Central Register of Controlled Trials (CENTRAL) to identify randomized controlled trials (RCTs) reporting the concentration of serum Hcy in metformin-treated adults. Meta-analysis was applied to assess the association between metformin and the changes of Hcy concentration. Twelve publications were included in this study. In the overall analysis, metformin administration was not statistically associated with the change of Hcy when compared with the control treatment (mean difference (MD), 0.40 μmol/L; 95% confidence interval (CI), −0.07~0.87 μmol/L, p = 0.10). In the subgroup analysis, metformin was significantly associated with an increased concentration of Hcy in the absence of exogenous supplementation of folic acid or B-group vitamins (MD, 2.02 μmol/L; 95% CI, 1.37~2.67 μmol/L, p < 0.00001), but with a decreased concentration of serum Hcy in the presence of these exogenous supplementations (MD, −0.74 μmol/L; 95% CI, −1.19~−0.30 μmol/L, p = 0.001). Therefore, although the overall effect of metformin on the concentration of serum Hcy was neutral, our results suggested that metformin could increase the concentration of Hcy when exogenous B-group vitamins or folic acid supplementation was not given.
PMCID: PMC5188453  PMID: 27941660
metformin; homocysteine; vitamin B12; folic acid; systematic review; meta-analysis
7.  Caspase-3 cleaved p65 fragment dampens NF-κB-mediated anti-apoptotic transcription by interfering with the p65/RPS3 interaction 
FEBS letters  2015;589(23):3581-3587.
Caspase-3-mediated p65 cleavage is believed to suppress nuclear factor-kappa B (NF-κB)-mediated anti-apoptotic transactivation in cells undergoing apoptosis. However, only a small percentage of p65 is cleaved during apoptosis, not in proportion to the dramatic reduction in NF-κB transactivation. Here we show that the p651-97 fragment generated by Caspase-3 cleavage interferes with ribosomal protein S3 (RPS3), an NF-κB “specifier” subunit, and selectively retards the nuclear translocation of RPS3, thus dampening the RPS3/NF-κB-dependent anti-apoptotic gene expression. Our findings reveal a novel cell fate determination mechanism to ensure cells undergo programed cell death through interfering with the RPS3/NF-κB-conferred anti-apoptotic transcription by the fragment from partial p65 cleavage by activated Caspase-3.
PMCID: PMC4655178  PMID: 26526615
Fate determination; Apoptosis; NF-κB; RPS3; Gene transcription; Caspase-3 cleavage
8.  Hysteroscopic management of a heterotopic pregnancy following uterine artery embolization: a case report 
Intra-uterine pregnancy coexisting with cervical pregnancy (heterotopic pregnancy) is a rare condition and its management is challenging because of the massive bleeding associated with cervical pregnancy. Uterine artery embolization followed by hysteroscopic removal of cervical and intra-uterine products of conception can theoretically prevent massive bleeding and provide a direct view during the removal. Hysteroscopic management following uterine artery embolization of heterotopic pregnancy after in vitro fertilization and embryo transfer is rarely reported.
Case presentation
A 33-year-old primigravida, Asian, married, nonsmoker, nonalcoholic woman presented with heavy vaginal bleeding 3 weeks after in vitro fertilization and embryo transfer with a documented history of two embryo implantations in her uterine cavity. Transvaginal ultrasonography revealed a gestational sac of 15 mm × 9 mm × 9 mm with cardiac activity, showing a 3.0-mm-diameter yolk sac in the uterine cavity and a 15 mm × 11 mm × 8 mm gestational sac with cardiac activity, showing a 2.9-mm-diameter yolk sac in the cervical canal. The bilateral uterine artery embolization followed by hysteroscopic removal of both the gestational products was successfully performed after our patient and her family chose to give up the intra-uterine pregnancy due to the risk of heavy bleeding associated with cervical pregnancy.
Uterine artery embolization followed by hysteroscopic removal of cervical and intra-uterine gestational products in the first trimester is safe and feasible, while preserving future fertility.
PMCID: PMC5111352  PMID: 27846865
Cervical pregnancy; Intra-uterine pregnancy; Heterotopic pregnancy; Hysteroscopy; Surgical management; Uterine artery embolization; Case report
9.  ATP-Competitive MLKL Binders Have No Functional Impact on Necroptosis 
PLoS ONE  2016;11(11):e0165983.
MLKL is a pore forming pseudokinase involved in the final stage of necroptosis, a form of programmed cell death. Its phosphorylation by RIPK3 is necessary for triggering necroptosis but not for triggering apoptosis, which makes it a unique target for pharmacological inhibition to block necroptotic cell death. This mechanism has been described as playing a role in disease progression in neurodegenerative and inflammatory diseases. A type II kinase inhibitor (cpd 1) has been described that reportedly binds to the MLKL pseudokinase domain and prevents necroptosis. Here we describe five compounds that bind to the MLKL ATP-binding site, however the four MLKL-selective compounds have no activity in rescuing cells from necroptosis. We use kinase selectivity panels, crystallography and a new conformationally sensitive method of measuring protein conformational changes (SHG) to confirm that the one previously reported compound that can rescue cells (cpd 1) is a non-selective type II inhibitor that also inhibits the upstream kinase RIPK1. Although this compound can shift the GFE motif of the activation loop to an “out” position, the accessibility of the key residue Ser358 in the MLKL activation loop is not affected by compound binding to the MLKL active site. Our studies indicate that an ATP-pocket inhibitor of the MLKL pseudokinase domain does not have any impact on the necroptosis pathway, which is contrary to a previously reported study.
PMCID: PMC5104457  PMID: 27832137
10.  FGF-Regulated ETV Transcription Factors Control FGF-SHH Feedback Loop in Lung Branching 
Developmental cell  2015;35(3):322-332.
The mammalian lung forms its elaborate tree-like structure following a largely stereotypical branching sequence. While a number of genes have been identified to play essential roles in lung branching, what coordinates the choice between branch growth and new branch formation has not been elucidated. Here we show that loss of FGF-activated transcription factor genes, Etv4 and Etv5 (collectively Etv), led to prolonged branch tip growth and delayed new branch formation. Unexpectedly, this phenotype is more similar to mutants with increased, rather than decreased FGF activity. Indeed, an increased Fgf10 expression is observed and reducing Fgf10 dosage can attenuate the Etv mutant phenotype. Further evidence indicates that ETV inhibits Fgf10 via directly promoting Shh expression. SHH in turn inhibits local Fgf10 expression and redirects growth, thereby initiating new branches. Together, our findings establish ETV as a key node in the FGF-ETV-SHH inhibitory feedback loop that dictates the rhythm of branching.
Graphical Abstract
PMCID: PMC4763945  PMID: 26555052
11.  Improved sensitization effect of sunitinib in cancer cells of the esophagus under hypoxic microenviroment 
Oncology Letters  2016;12(6):4671-4676.
Radiotherapy is widely used in esophageal squamous cell carcinoma (ESCC) treatment. Promoting the radiation sensitivity of cancer cells is required. Recent studies have shown that sunitinib can inhibit the growth of several cancer lines. However, few studies on the radiosensitive effect of sunitinib on ESCC cells under hypoxic conditions have been conducted. In the present study, the radiosensitive effects of sunitinib on human ESCC cells were assessed, and the underlying mechanisms were explored. ESCC cells were exposed to hypoxia and treated with sunitinib at different concentrations prior to irradiation. Sunitinib potently inhibited ESCC cell proliferation in an MTT assay. In a clonogenic survival assay, sunitinib sensitized hypoxic ESCC cells to radiation, with sensitizing enhancement ratios of 1.31–1.59. In addition, sunitinib promoted the apoptosis of ESCC cells, but did not alter their cell cycle distribution. Radiosensitization was accompanied by inhibition of the radiation-induced upregulation of hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) expression. Thus, sunitinib confers radiosensitivity to esophageal cancer cells, which is associated with the downregulation of HIF-1α and VEGF expression. Sunitinib can be a promising radiosensitizer for esophageal cancer radiotherapy.
PMCID: PMC5228423
sunitinib; esophageal cancer; hypoxia; radiosensitization; HIF-1α
12.  Multiple organ dysfunction and systemic inflammation after spinal cord injury: a complex relationship 
Spinal cord injury (SCI) is a devastating event that results in significant physical disabilities for affected individuals. Apart from local injury within the spinal cord, SCI patients develop a variety of complications characterized by multiple organ dysfunction or failure. These disorders, such as neurogenic pain, depression, lung injury, cardiovascular disease, liver damage, kidney dysfunction, urinary tract infection, and increased susceptibility to pathogen infection, are common in injured patients, hinder functional recovery, and can even be life threatening. Multiple lines of evidence point to pathological connections emanating from the injured spinal cord, post-injury systemic inflammation, and immune suppression as important multifactorial mechanisms underlying post-SCI complications. SCI triggers systemic inflammatory responses marked by increased circulation of immune cells and pro-inflammatory mediators, which result in the infiltration of inflammatory cells into secondary organs and persistence of an inflammatory microenvironment that contributes to organ dysfunction. SCI also induces immune deficiency through immune organ dysfunction, resulting in impaired responsiveness to pathogen infection. In this review, we summarize current evidence demonstrating the relevance of inflammatory conditions and immune suppression in several complications frequently seen following SCI. In addition, we highlight the potential pathways by which inflammatory and immune cues contribute to multiple organ failure and dysfunction and discuss current anti-inflammatory approaches used to alleviate post-SCI complications. A comprehensive review of this literature may provide new insights into therapeutic strategies against complications after SCI by targeting systemic inflammation.
PMCID: PMC5053065  PMID: 27716334
Spinal cord injury; Multiple organ dysfunction; Systemic inflammatory response syndrome; Immune depression syndrome; Post-injury infection
13.  Development-Dependent Regulation of Molecular Chaperones after Hypoxia-Ischemia 
Neurobiology of disease  2015;82:123-131.
Cellular stress response after hypoxia-Ischemia (HI) may be substantially different between immature and mature brain. To study this phenomenon, postnatal day 7 (P7) and P26 rats were subjected to HI followed by different periods of recovery. Nuclear accumulation of heat-shock transcription factor-1 (HSF1) and expression of molecular chaperone proteins and mRNAs were analyzed by in situ hybridization, Western blotting and confocal microscopy. Nuclear accumulation of HSF1 protein and induction of hsp70 mRNA occurred dramatically in P26 neurons, but minimally in P7 neurons and moderately in microglial cells after HI. Consistently, the level of HSF1 was significantly higher in P26 brain samples, compared with that in P7 brain. Translation of hsp70 mRNA into proteins in P26 mature neurons were seen at 4 h and peaked at 24 h, when some neurons had already died after HI. Induction of ER glucose-regulated protein-78 (grp78) and mitochondrial hsp60 mRNAs and proteins was moderate and occurred also only in P26 mature brain after HI. These results suggest that the cellular stress response after HI is development-dependent, being pronounced in mature but virtually negligible in neonatal neurons. Therefore, the effectiveness of therapeutic strategies targeting the stress pathway against HI may be significantly different between immature and mature brains. The delayed induction of molecular chaperones in mature brain may be somewhat late for protecting HI neurons from acute HI injury.
PMCID: PMC4641006  PMID: 26070787
hypoxia-ischemia; brain development; neonatal; neuronal death; molecular chaperones; protein aggregation; ER stress
14.  LCL161 increases paclitaxel-induced apoptosis by degrading cIAP1 and cIAP2 in NSCLC 
LCL161, a novel Smac mimetic, is known to have anti-tumor activity and improve chemosensitivity in various cancers. However, the function and mechanisms of the combination of LCL161 and paclitaxel in non-small cell lung cancer (NSCLC) remain unknown.
Cellular inhibitor of apoptotic protein 1 and 2 (cIAP1&2) expression in NSCLC tissues and adjacent non-tumor tissues were assessed by immunohistochemistry. The correlations between cIAP1&2 expression and clinicopathological characteristics, prognosis were analyzed. Cell viability and apoptosis were measured by MTT assays and Flow cytometry. Western blot and co-immunoprecipitation assay were performed to measure the protein expression and interaction in NF-kB pathway. siRNA-mediated gene silencing and caspases activity assays were applied to demonstrate the role and mechanisms of cIAP1&2 and RIP1 in lung cancer cell apoptosis. Mouse xenograft NSCLC models were used in vivo to determine the therapeutic efficacy of LCL161 alone or in combination with paclitaxel.
The expression of cIAP1 and cIAP2 in Non-small cell lung cancer (NSCLC) tumors was significantly higher than that in adjacent normal tissues. cIAP1 was highly expressed in patients with late TNM stage NSCLC and a poor prognosis. Positivity for both cIAP1 and cIAP2 was an independent prognostic factor that indicated a poorer prognosis in NSCLC patients. LCL161, an IAP inhibitor, cooperated with paclitaxel to reduce cell viability and induce apoptosis in NSCLC cells. Molecular studies revealed that paclitaxel increased TNFα expression, thereby leading to the recruitment of various factors and the formation of the TRADD-TRAF2-RIP1-cIAP complex. LCL161 degraded cIAP1&2 and released RIP1 from the complex. Subsequently, RIP1 was stabilized and bound to caspase-8 and FADD, thereby forming the caspase-8/RIP1/FADD complex, which activated caspase-8, caspase-3 and ultimately lead to apoptosis. In nude mouse xenograft experiments, the combination of LCL161 and paclitaxel degraded cIAP1,2, activated caspase-3 and inhibited tumor growth with few toxic effects.
Thus, LCL161 could be a useful agent for the treatment of NSCLC in combination with paclitaxel.
PMCID: PMC5062899  PMID: 27737687
NSCLC; cIAP; LCL161; Paclitaxel; Apoptosis
15.  Postoperative prophylactic hepatic arterial infusion chemotherapy for stage III colorectal cancer: a retrospective study 
OncoTargets and therapy  2016;9:5897-5902.
Radical resection is the main treatment for colorectal cancer (CRC), but metastasis or recurrence is common in which liver metastasis accounted for 83% of the cases. Therefore, the prognosis of patients with advanced CRC may be improved if liver metastasis is prevented. This study aims to investigate the efficacy of hepatic arterial infusion chemotherapy (HAIC) on liver metastases of stage III CRC patients after curative resection.
Between 2002 and 2008, 287 stage III CRC patients who had undergone radical resection were included in this study. According to postoperative adjuvant chemotherapy modality, these patients were divided into two groups. Patients in the combined therapy group received two cycles of HAIC plus four cycles of systemic chemotherapy, while patients in the monotherapy group received six cycles of systemic chemotherapy alone. The HAIC regimen consisted of hepatic arterial infusion of oxaliplatin (OXA, 85 mg/m2) on day 1 and 5-fluorouracil (5-FU, 2,400 mg/m2) on days 2 and 3 followed by a vein infusion of folinic acid (FA, 200 mg/m2) as a 2-hour infusion on days 2 and 3. The systemic chemotherapy regimen consisted of a 2-hour infusion of OXA (85 mg/m2) on day 1 followed by FA (200 mg/m2) as a 2-hour infusion on days 2 and 3, and by 5-FU (2,400 mg/m2) as a 48-hour infusion. This was repeated every 4 weeks. All cases were followed up for 5 years or until death. The 5-year overall survival, disease-free survival, liver metastases-free survival, and the overall liver metastases rates were retrospectively compared.
Significant differences were found in the 5-year overall survival (combined therapy, 70.71%; monotherapy, 57.14%; P=0.014), disease-free survival (combined therapy, 69.29%; monotherapy, 55.78%; P=0.021), and liver metastases-free survival rates (combined therapy, 70%; monotherapy, 56.46%; P=0.019).
Prophylactic adjuvant HAIC can prevent metachronous liver metastases and improve the prognosis of patients with stage III CRC after curative resection.
PMCID: PMC5045227  PMID: 27713643
colorectal cancer; hepatic arterial infusion chemotherapy; liver metastases; chemotherapy
16.  Sam68 Is Required for DNA Damage Responses via Regulating Poly(ADP-ribosyl)ation 
PLoS Biology  2016;14(9):e1002543.
The rapid and robust synthesis of polymers of adenosine diphosphate (ADP)-ribose (PAR) chains, primarily catalyzed by poly(ADP-ribose) polymerase 1 (PARP1), is crucial for cellular responses to DNA damage. However, the precise mechanisms through which PARP1 is activated and PAR is robustly synthesized are not fully understood. Here, we identified Src-associated substrate during mitosis of 68 kDa (Sam68) as a novel signaling molecule in DNA damage responses (DDRs). In the absence of Sam68, DNA damage-triggered PAR production and PAR-dependent DNA repair signaling were dramatically diminished. With serial cellular and biochemical assays, we demonstrated that Sam68 is recruited to and significantly overlaps with PARP1 at DNA lesions and that the interaction between Sam68 and PARP1 is crucial for DNA damage-initiated and PARP1-conferred PAR production. Utilizing cell lines and knockout mice, we illustrated that Sam68-deleted cells and animals are hypersensitive to genotoxicity caused by DNA-damaging agents. Together, our findings suggest that Sam68 plays a crucial role in DDR via regulating DNA damage-initiated PAR production.
The RNA-binding protein Sam68 has unexpected function in the early signaling of DNA damage, and is critical for the activation and regulation of poly(ADP-ribose) polymerase 1 in response to DNA damage.
Author Summary
Maintaining genome integrity is crucial for all organisms, and failure to do so can lead to fatal diseases such as cancer. Exposure to challenging environments can induce DNA strand breaks or other lesions; thus, rapid and appropriate DNA damage responses (DDRs) need to be in place to detect and repair the damage. Cellular networks use a variety of signaling molecules and post-translational modifications that are crucial for the signaling of DNA breaks to repair machineries. Poly(adenosine diphosphate [ADP]-ribosyl)ation (PARylation) and activation of the enzyme poly(ADP-ribose) polymerase 1 (PARP1) is a post-translational modification that occurs within seconds upon DNA damage detection and triggers downstream DDR signaling; however, it remains obscure whether other molecules, beyond DNA strand breaks, stimulate or control PARP1 activity. We report here that a novel DDR signaling molecule, Src-associated substrate during mitosis of 68 kDa (Sam68), has a crucial function in governing the DNA damage-initiated PARP1 activation and polymers of ADP-ribose (PAR) production. We show that Sam68 is recruited to and significantly overlaps with PARP1 at DNA lesions and that the Sam68-PARP1 interaction is critical for DNA damage-initiated PARP1 activation and PAR production both in vitro and in vivo. Sam68-deleted cells and animals have a diminished PAR-dependent DNA repair signaling and are hypersensitive to genotoxicity caused by DNA-damaging agents. Hence, our data reveal an unexpected function for Sam68 in DNA damage-initiated early signaling and provide a novel mechanism on the activation and regulation of PARP1 in DDR.
PMCID: PMC5026359  PMID: 27635653
17.  Glycitin regulates osteoblasts through TGF-β or AKT signaling pathways in bone marrow stem cells 
The aim of the present study was to examine the effect of glycitin on the regulation of osteoblasts from bone marrow stem cells (BMSCs) through transforming growth factor (TGF)-β or protein kinase B (AKT) signaling pathways. BMSCs were extracted from New Zealand white rabbits and used to analyze the effect of glycitin on BMSCs. BMSCs were cleared using xylene and observed via light microscopy. BMSCs were subsequently induced with glycitin (0.01, 0.5, 1, 5 and 10 µM) for 7 days, and stained with Oil Red O. The mechanism of action of glycitin on BMSCs was investigated, in which contact with collagen type I (Col I), alkaline phosphatase (ALP), TGF-β and AKT was studied. Firstly, BMSCs appeared homogeneously mazarine blue, and which showed that BMSCs were successful extracted. Administration of glycitin increased cell proliferation and promoted osteoblast formation from BMSCs. Furthermore, glycitin activated the gene expression of Col I and ALP in BMSCs. Notably, glycitin suppressed protein expression of TGF-β and AKT in BMSCs. These results indicated that glycitin may regulate osteoblasts through TGF-β or AKT signaling pathways in BMSCs.
PMCID: PMC5103745  PMID: 27882117
glycitin; osteoblast; bone marrow stem cells; transforming growth factor-β 1; protein kinase B
18.  Alpha-glucosidase inhibitors and hepatotoxicity in type 2 diabetes: a systematic review and meta-analysis 
Scientific Reports  2016;6:32649.
Alpha-glucosidase inhibitors (AGIs) was reported to be associated with several rare adverse hepatic events, but with inconsistent results. We aimed to investigate the risk of hepatotoxicity associated with the use of AGIs in patients with type 2 diabetes mellitus (T2DM), and performed a systematic review and meta-analysis. Fourteen studies (n = 2881) were eligible, all of which were RCTs. Meta-analysis of data regarding elevation of more than 3-fold the upper limit of normal (ULN) of AST and ALT showed statistically significant differences between AGIs treatment versus control (OR 6.86, 95% CI 2.50 to 18.80; OR 6.48, 95% CI 2.40 to 17.49). Subgroup analyses of elevation of more than 1.8-fold ULN of AST and ALT by dose of AGIs showed differential effects on AST and ALT (AST: OR 0.38 vs 7.31, interaction P = 0.003; ALT: OR 0.32 vs 4.55, interaction p = 0.02). Meta-analysis showed that AGIs might increase the risk of hepatotoxicity, and higher dose appeared to be associated with higher risk of hepatotoxicity. However, the evidence is limited with surrogate measures (i.e. ALT and AST), and no clinically important adverse events were observed.
PMCID: PMC5011653  PMID: 27596383
19.  Impaired Capacity of Fibroblasts to Support Airway Epithelial Progenitors in Bronchiolitis Obliterans Syndrome 
Chinese Medical Journal  2016;129(17):2040-2044.
Bronchiolitis obliterans syndrome (BOS) often develops in transplant patients and results in injury to the respiratory and terminal airway epithelium. Owing to its rising incidence, the pathogenesis of BOS is currently an area of intensive research. Studies have shown that injury to the respiratory epithelium results in dysregulation of epithelial repair. Airway epithelial regeneration is supported by stromal cells, including fibroblasts. This study aimed to investigate whether the supportive role of lung fibroblasts is altered in BOS.
Suspensions of lung cells were prepared by enzyme digestion. Lung progenitor cells (LPCs) were separated by fluorescence-activated cell sorting. Lung fibroblasts from patients with BOS or healthy controls were mixed with sorted mouse LPCs to compare the colony-forming efficiency of LPCs by counting the number of colonies with a diameter of ≥50 μm in each culture. Statistical analyses were performed using the SPSS 17.0 software (SPSS Inc., USA). The paired Student's t-test was used to test for statistical significance.
LPCs were isolated with the surface phenotype of CD31- CD34- CD45- EpCAM+ Sca-1+. The colony-forming efficiency of LPCs was significantly reduced when co-cultured with fibroblasts isolated from patients with BOS. The addition of SB431542 increased the colony-forming efficiency of LPCs to 1.8%; however, it was still significantly less than that in co-culture with healthy control fibroblasts (P < 0.05).
The epithelial-supportive capacity of fibroblasts is impaired in the development of BOS and suggest that inefficient repair of airway epithelium could contribute to persistent airway inflammation in BOS.
PMCID: PMC5009585  PMID: 27569228
Bronchiolitis Obliterans Syndrome; Fibroblasts; Lung Progenitor Cells; Proliferation
20.  The insights of Let‐7 miRNAs in oncogenesis and stem cell potency 
The ability of the classic tumour‐suppressive let‐7 family to inhibit carcinogenesis, tumour progression, recurrence and pluripotency of cancer stem cells has generated significant interest in the field of cancer research. Through suppressing and degrading downstream‐targeted mRNAs, let‐7 affected most aspects of cell biology. It is perplexing how let‐7 affects oncogenesis, as the large influx of new miRNAs and other kinds of non‐coding RNAs are continuously defined. In this review, we delineate the complex functions of let‐7 and discuss the future direction of let‐7 research.
PMCID: PMC4988292  PMID: 27097729
Let‐7 miRNAs; regulatory loops; non‐coding RNAs; cancer stem cells; DNA methylation; anti‐cancer research; clinical application
21.  Activated leukocyte cell adhesion molecule regulates the interaction between pancreatic cancer cells and stellate cells 
Molecular Medicine Reports  2016;14(4):3627-3633.
Activated leukocyte cell adhesion molecule (ALCAM/CD166) is a transmembrane glycoprotein that is involved in tumor progression and metastasis. In the present study, the expression and functional role of ALCAM in pancreatic cancer cells and pancreatic stellate cells (PSCs) was investigated. Tissue specimens were obtained from patients with pancreatic ductal adenocarcinoma (n=56) or chronic pancreatitis (CP; n=10), who underwent pancreatic resection, and from normal pancreatic tissue samples (n=10). Immunohistochemistry was used to analyze the localization and expression of ALCAM in pancreatic tissues. Subsequently, reverse transcription-quantitative polymerase chain reaction and immunoblotting were applied to assess the expression of ALCAM in pancreatic cancer Panc-1 and T3M4 cells, as well as in PSCs. An enzyme-linked immunosorbent assay was used to measure ALCAM levels in cell culture medium stimulated by hypoxia, tumor necrosis factor (TNF)-α and transforming growth factor-β. Silencing of ALCAM was performed using ALCAM small interfering (si)RNA and immunocytochemistry was used to analyze the inhibition efficiency. An invasion assay and a cell interaction assay were performed to assess the invasive ability and co-cultured adhesive potential of Panc-1 and T3M4 cells, as well as PSCs. Histologically, ALCAM expression was generally weak or absent in pancreatic cancer cells, but was markedly upregulated in PSCs in pancreatic cancer tissues. ALCAM was highly expressed in PSCs from CP tissues and PSCs surrounding pancreatic intraepithelial neoplasias, as well as in pancreatic cancer cells. ALCAM mRNA was highly expressed in PSCs, with a low to moderate expression in T3M4 and Panc-1 cells. Similar to the mRNA expression, immunoblotting demonstrated that ALCAM protein levels were high in PSCs and T3M4 cells, but low in Panc-1 cells. The expression of TNF-α increased, while hypoxia decreased the secretion of ALCAM in pancreatic cancer Panc-1 and T3M4 cells, and also in PSCs. Silencing of ALCAM by siRNA revealed no significant alteration in the invasion of pancreatic cancer cells, however, it inhibited the invasive ability of PSCs, and decreased the interaction between Panc-1 cells and PSCs. In conclusion, ALCAM is upregulated in PSCs of pancreatic cancer tissues, suggesting a potential role of ALCAM in regulating pancreatic cancer cell-PSC interactions.
PMCID: PMC5042774  PMID: 27573419
activated leukocyte cell adhesion molecule; CD166; pancreatic cancer cells; pancreatic stellate cells; microenvironment
22.  Attachment Security Balances Perspectives: Effects of Security Priming on Highly Optimistic and Pessimistic Explanatory Styles 
Frontiers in Psychology  2016;7:1269.
Highly optimistic explanatory style (HOES) and highly pessimistic explanatory style (HPES) are two maladaptive ways to explain the world and may have roots in attachment insecurity. The current study aims to explore the effects of security priming – activating supportive representations of attachment security – on ameliorating these maladaptive explanatory styles. 57 participants with HOES and 57 participants with HPES were randomized into security priming and control conditions. Their scores of overall optimistic attribution were measured before and after priming. Security priming had a moderating effect: the security primed HOES group exhibited lower optimistic attribution, while the security primed HPES group evinced higher scores of optimistic attribution. Furthermore, the security primed HOES group attributed positive outcomes more externally, while the security primed HPES group attributed successful results more internally. The results support the application of security priming interventions on maladaptive explanatory styles. Its potential mechanism and directions for future study are also discussed.
PMCID: PMC4997126  PMID: 27610092
optimistic explanatory style; pessimistic explanatory style; attachment security; security priming; self-serving attribution; self-deprecating attribution; self-enhancing defense
23.  Whole Genome Sequencing Identifies a Missense Mutation in HES7 Associated with Short Tails in Asian Domestic Cats 
Scientific Reports  2016;6:31583.
Domestic cats exhibit abundant variations in tail morphology and serve as an excellent model to study the development and evolution of vertebrate tails. Cats with shortened and kinked tails were first recorded in the Malayan archipelago by Charles Darwin in 1868 and remain quite common today in Southeast and East Asia. To elucidate the genetic basis of short tails in Asian cats, we built a pedigree of 13 cats segregating at the trait with a founder from southern China and performed linkage mapping based on whole genome sequencing data from the pedigree. The short-tailed trait was mapped to a 5.6 Mb region of Chr E1, within which the substitution c. 5T > C in the somite segmentation-related gene HES7 was identified as the causal mutation resulting in a missense change (p.V2A). Validation in 245 unrelated cats confirmed the correlation between HES7-c. 5T > C and Chinese short-tailed feral cats as well as the Japanese Bobtail breed, indicating a common genetic basis of the two. In addition, some of our sampled kinked-tailed cats could not be explained by either HES7 or the Manx-related T-box, suggesting at least three independent events in the evolution of domestic cats giving rise to short-tailed traits.
PMCID: PMC4997960  PMID: 27560986
24.  Distinct response of the hepatic transcriptome to Aflatoxin B1 induced hepatocellular carcinogenesis and resistance in rats 
Scientific Reports  2016;6:31898.
Aflatoxin is a natural potent carcinogen and a major cause of liver cancer. However, the molecular mechanisms of hepatocellular carcinogenesis remain largely unexplored. In this study, we profiled global gene expression in liver tissues of rats that developed hepatocellular carcinoma (HCC) from aflatoxin B1 (AFB1) administration and those that were AFB1-resistant, as well as rats without AFB1 exposure as a control. AFB1 exposure resulted in extensive perturbation in gene expression with different functions in HCC and AFB1 resistance (AR) samples. The differentially expressed genes (DEGs) in HCC sample were enriched for cell proliferation, cell adhesion and vasculature development that largely contribute to carcinogenesis. Anti-apoptosis genes were up-regulated in HCC sample whereas apoptosis-induction genes were up-regulated in AR sample. AFB1 exposure also caused extensive alteration in expression level of lncRNAs. Among all the 4511 annotated lncRNAs, half of them were highly expressed only in HCC sample and up-regulated a group of protein-coding genes with cancer-related functions: apoptosis regulation, DNA repair, and cell cycle. Intriguingly, these genes were down-regulated by lncRNAs highly expressed in AR sample. Collectively, apoptosis is the critical biological process for carcinogenesis in response to AFB1 exposure through changes in expression level of both protein-coding and lncRNA genes.
PMCID: PMC4992951  PMID: 27545718
25.  Ultrasound imaging of splenomegaly as a proxy to monitor colon tumor development in Apc min716/+ mice 
Cancer Medicine  2016;5(9):2469-2476.
Animal models of colon cancer are widely used to understand the molecular mechanisms and pathogenesis of the disease. These animal models require a substantial investment of time and traditionally necessitate the killing of the animal to measure the tumor progression. Several in vivo imaging techniques are being used in both human clinics and preclinical studies, albeit at high cost and requiring particular expertise. Here, we report that the progression of splenomegaly coincides with and positively correlates to colon tumor development in Apc min716/+ mice expressing a mutant gene encoding an adenomatous polyposis coli protein truncated at amino acid 716. Ultrasound image‐based spleen size measurement precisely mirrors splenomegaly development in vivo in the tumor‐laden Apc min716/+ mice. Moreover, the spleen dimensions extracted from the ultrasound sonograms are positively correlated with normalized spleen weight and the number and area of colon tumors. Hence, we propose measuring the spleen size in vivo by ultrasound imaging as a novel approach to estimate splenomegaly development and to indirectly monitor colon tumor development in Apc min716/+ mice. The widespread use of ultrasound machines in the laboratory setting, coupled with the fact that it is a noninvasive method, make it a straightforward and useful tool for monitoring the experimental progress of colon cancer in mice and determining end points without killing animals strictly for diagnostics purposes.
PMCID: PMC5055147  PMID: 27485505
Colon tumor; in vivo imaging; splenomegaly; ultrasound

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