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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 955 records · Page 53
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Etoposide induced NMI promotes cell apoptosis by activating the ARF-p53 signaling pathway in lung carcinoma

Highlights: • Etoposide inducescell apoptosis and increases the expression of NMI and ARF in A549 cells. • NMI positivelyregulates ARF protein expression and inhibits the cell proliferation. • Etoposide enhances the interaction between NMI and ARF andpromotes transcriptional activity ofp53. • Etoposide-induced NMI inhibits the proliferation and enhancesapoptosis by activating the p53 signaling. • Our results showed thatNMI has a critical role in suppressing lung carcinoma progression. Lung carcinoma is one of the leading causes of cancer-related death. The N-Myc and STATs interactor (NMI) has been reported to take participate in lots of physiological processes, but the involvement and functional mechanisms of NMI in lung carcinoma are poorly understood. In this study, we found that etoposide induces proliferation suppression, cell apoptosis and increases caspase-3 activity in A549 cells. Furthermore, etoposide treatment up-regulates the expression of NMI and ARF, enhances the interaction of NMI and ARF and promotes the p53 transcriptional activities. By contrast, when silencing NMI, the proliferation suppression and cell apoptosis caused by etoposide were repressed and the p53 signaling pathway activation was also suppressed. These investigations demonstrated etoposide-induced NMI can suppress tumor proliferation and promote cell apoptosis by activating the ARF-p53 signaling pathway in lung carcinoma. Our results provide an alternative mechanism for etoposide in lung carcinoma and suggest NMI has a critical role in suppressing lung carcinoma progression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

3-(Naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride attenuates NLRP3 inflammasome-mediated signaling pathway in lipopolysaccharide-stimulated BV2 microglial cells

Highlights: • KHG26792 attenuated LPS-induced TNF-α, IL-1β, and IL-6 level in BV2 cells. • KHG26792 attenuated LPS-induced ROS and nitrotyrosine level. • KHG26792 attenuated LPS-induced damage in mitochondrial potential. • KHG26792 attenuated LPS-induced expression of NLRP3, activated caspase-1, and ASC. • KHG26792 attenuated LPS-induced ATP level through P2X7 receptor. The nucleotide-binding and oligomerization domain-like receptor containing a pyrin domain 3 (NLRP3) inflammasome is a multiprotein complex with a role in innate immune responses. NLRP3 inflammasome dysfunction is a common feature of chronic inflammatory diseases. Microglia activation is also associated with neuroinflammatory pathologies. We previously reported that 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride (KHG26792) reduced hypoxia-induced toxicity by modulating inflammation. However, no studies have elucidated the precise mechanisms for the anti-inflammatory action of KHG26792, in particular via inflammasome mediation. This study investigated the effects of KHG26792 on the inflammasome-mediated signaling pathway in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. KHG26792 significantly attenuated several inflammatory responses including tumor necrosis factor-α, interleukin-1β, interleukin-6, reactive oxygen species, and mitochondrial potential in these cells. KHG26792 also suppressed LPS-induced increase NLRP3, activated caspase-1, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) levels. Furthermore, KHG26792 successfully blocked LPS-activated adenosine triphosphate (ATP) level, likely through the purinergic receptor P2X ligand-gated ion channel 7 (P2X7) receptor. Our results suggest that the anti-inflammatory functions of KHG26792 may be, at least in part, due to regulation of the P2X7R/NLRP3-mediated signaling pathway during microglial activation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

LncRNA COL1A2-AS1 inhibits the scar fibroblasts proliferation via regulating miR-21/Smad7 pathway

Highlights: • LncRNA COL1A2-AS1 is upregulated in hypertrophic scar tissue and fibroblasts. • LncRNA COL1A2-AS1 suppresses fibroblasts proliferation by promoting Smad7 expression. • miR-21 is involved in lncRNA COL1A2-AS1-induced expression of Smad7. • Overexpression of miR-21 attenuates COL1A2-AS1–mediated proliferation suppression of hypertrophic scar fibroblasts. lncRNA COL1A2-AS1 (COL1A2 antisense RNA 1), a lncRNA overexpressed in hypertrophic scar, has been demonstrated to be involved in the hypertrophic scar formation. However, the mechanisms of lncRNA COL1A2-AS1 inhibiting the scar fibroblasts proliferation remains not well understood. In this study, we demonstrated that lncRNA COL1A2-AS1 was upregulated in hypertrophic scar tissue and fibroblasts, and suppressed fibroblasts proliferation by promoting Smad7 expression. Furthermore, we found that miR-21 was involved in lncRNA COL1A2-AS1-induced expression of Smad7, by which COL1A2-AS1 acted as endogenous sponge to adsorb miR-21 and in turn regulated Smad7 and a cascade of molecular to play a protective role in hypertrophic scar. In addition, overexpression of miR-21 attenuated COL1A2-AS1-mediated proliferation suppression of hypertrophic scar fibroblasts. In conclusion, our study demonstrated that COL1A2-AS1/miR-21/Smad pathway plays an important role in inhibiting hypertrophic scar formation, and suggested this novel pathway may be a new target for hypertrophic scar treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Tetrahydroxystilbene glucoside modulates amyloid precursor protein processing via activation of AKT-GSK3β pathway in cells and in APP/PS1 transgenic mice

Alternative splicing of amyloid precursor protein (APP) exon 7 generates the isoforms containing a Kunitz protease inhibitor (KPI) domain. APP-KPI levels in the brain are correlated with amyloid beta (Aβ) production. Here, we determined the effect of Tetrahydroxystilbene glucoside (TSG) on the AKT-GSK3β pathway. We found GSK3β increased APP-KPI inclusion level and interacted with the splicing factor ASF. TSG was intragastrically administered to 5-month-old APP/PS1 transgenic mice for 12 months. We found that the activated the AKT-GSK3β signaling pathway suppressed APP-KPI inclusion. Moreover, TSG treatment attenuated amyloid deposition in APP/PS1 mice. This study demonstrates the neuroprotective effect of TSG on APP expression, suggesting that TSG may be beneficial for AD prevention and treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Umbilical cord-derived mesenchymal stem cells alleviated inflammation and inhibited apoptosis in interstitial cystitis via AKT/mTOR signaling pathway

Highlights: • UC-MSCs alleviated inflammation in rat model and cell model of IC. • UC-MSCs promoted proliferation of urothelium. • UC-MSCs inhibited apoptosis of urothelium. • UC-MSCs activated AKT/mTOR signaling pathway to cure IC. Interstitial cystitis (IC) is a bladder syndrome characterized by pelvic pain and urinary frequency without infection or other identifiable pathology. There are no effective treatments to cure IC. This study investigated the effects of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) injection on IC rat model. Furthermore, we used a coculture system to find the possible molecular mechanism on the human uroepithelial cells (SV-HUC-1), which was the cell model of IC. A rat model of IC was established via systemic injection with cyclophosphamide (CYP) and a cell model of IC was induced by being exposed to tumor necrosis factor (TNF)-α (10 ng/ml). After one week, UC-MSCs injection significantly ameliorated the bladder voiding function in IC rat model. And the Histo- and immunohistochemical analyses showed that UC-MSCs can repair impaired bladder, reduce mast cell infiltration and inhibit apoptosis of urothelium. ELISA results showed that UC-MSCs can decrease IL-1β, IL-6 and TNF-α in bladder. In the coculture system, UC-MSCs can promote proliferation of impaired SV-HUC-1 cells, and inhibit apoptosis. However, while knocked down EGF secreted by UC-MSCs with siRNA, the effects would be weaken. Western blot showed that UC-MSCs increase protein expression levels of p-AKT and p-mTOR in SV-HUC-1 cells, and decrease the levels of cleaved caspase-3. Taken together, we provide evidence that UC-MSCs therapy can successfully alleviate IC in a preclinical animal Model and cell model by alleviating inflammation, promoting proliferation and inhibiting apoptosis. In addition, we demonstrate that the AKT/mTOR signaling pathway was activated.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Secretogranin III promotes angiogenesis through MEK/ERK signaling pathway

Highlights: • Scg3 promotes endothelial proliferation, migration and tube formation. • MEK inhibitor blocks Scg3-induced angiogenesis. • ERK inhibitor suppresses Scg3-induced endothelial proliferation and migration. • MEK/ERK signaling pathway is critical to Scg3-induced angiogenesis. Secretogranin III (Scg3) was recently discovered as the first highly diabetic retinopathy-associated angiogenic factor, and its neutralizing antibody alleviated the disease with high efficacy in diabetic mice. Investigation of its molecular mechanisms will facilitate the translation of this novel therapy. Scg3 was reported to induce the phosphorylation of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK). Here we characterized the importance of MEK/ERK activation to Scg3 angiogenic activity. Our results showed that MEK inhibitor PD98059 blocked Scg3-induced proliferation of human umbilical vein endothelial cells (HUVECs). This finding was corroborated by PD98059 inhibition of HUVEC migration and tube formation. Furthermore, ERK inhibitor SCH772984 also suppressed Scg3-induced proliferation and migration of HUVECs. Taken together, these findings suggest that MEK-ERK pathway plays an important role in Scg3-induced angiogenesis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Hydrogen protects against hyperoxia-induced apoptosis in type II alveolar epithelial cells via activation of PI3K/Akt/Foxo3a signaling pathway

Highlights: • Hydrogen exerts a protective effect in hyperoxia-induced apoptosis of AECIIs. • Hydrogen exerts anti-apoptotic effects in hyperoxia-induced injury of AECIIs. • Hydrogen promotes the expression of CyclinD1 in hyperoxia-induced injury of AECIIs. • Hydrogen potently activates the PI3K/Akt/FoxO3a pathway in hyperoxia-induced apoptosis of AECIIs. Oxidative stress is regarded as a key regulator in the pathogenesis of prolonged hyperoxia-induced lung injury, which causes injury to alveolar epithelial cells and eventually leads to development of bronchopulmonary dysplasia (BPD). Many studies have shown that hydrogen has a protective effect in a variety of cells. However, the mechanisms by which hydrogen rescues cells from damage due to oxidative stress in BPD remains to be fully elucidated. This study sought to evaluate the effects of hydrogen on hyperoxia-induced lung injury and to investigate the underlying mechanism. Primary type II alveolar epithelial cells (AECIIs) were divided into four groups: control (21% oxygen), hyperoxia (95% oxygen), hyperoxia + hydrogen, and hyperoxia + hydrogen + LY294002 (a PI3K/Akt inhibitor). Proliferation and apoptosis of AECIIs were assessed using MTS assay and flow cytometry (FCM), respectively. Gene and protein expression were detected by quantitative polymerase chain reaction (q-PCR) and western blot analysis. Stimulation with hyperoxia decreased the expression of P-Akt, P- FoxO3a, cyclinD1 and Bcl-2. Hyperoxic conditions increased levels of Bim, Bax, and Foxo3a, which induced proliferation restriction and apoptosis of AECIIs. These effects of hyperoxia were reversed with hydrogen pretreatment. Furthermore, the protective effects of hydrogen were abrogated by PI3K/Akt inhibitor LY294002. The results indicate that hydrogen protects AECIIs from hyperoxia-induced apoptosis by inhibiting apoptosis factors and promoting the expression of anti-apoptosis factors. These effects were associated with activation of the PI3K/Akt/FoxO3a pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

MicroRNA-126 alleviates endothelial cells injury in atherosclerosis by restoring autophagic flux via inhibiting of PI3K/Akt/mTOR pathway

Highlights: • MiR-126 overexpression induced by miR-126 mimics reverses ox-LDL-induced HUVECs injury. • Ox-LDL induces the impairment of autophagy flux in HUVECs. • MiR-126 mimics mitigate ox-LDL-induced HUVECs injury through rescuing autophagy flux. • MiR-126 mimics restore ox-LDL-induced impaired autophagy flux through inhibiting PI3K/Akt/mTOR pathway in HUVECs. MicroRNAs (miRNAs) have emerged as critical modulators of ECs function and play a vital role in the development of cardiovascular disease. Among them, miR-126 is a crucial regulator of atherosclerosis. Endothelial cells (ECs) death and autophagy have been described in cells to cope with the progression of atherosclerosis. Hence, the aim of this study is to investigate the effects of miR-126 on atherosclerosis in oxidized low-density lipoprotein (ox-LDL)-stimulated human umbilical vein endothelial cells (HUVECs) and the potential roles of autophagy flux in these processes. Our results showed that miR-126 level was significantly reduced in ox-LDL-treated HUVECs and miR-126 overexpression induced by miR-126 mimics remarkably blocked ox-LDL-induced HUVECs injury as evidenced by the reduced cell viability, and the increased LDH release, caspase-3 activity and apoptosis ratio. In addition, ox-LDL increased LC3-II, Beclin 1, and p62 expressions in HUVECs, while these changes were nullified in the presence of treatment with bafilomycin A1 (BafA1, an inhibit autophagic flux inhibitor). However, we found that ox-LDL-induced impaired autophagy flux was recused by miR-126 mimics. Subsequently, we found that Bafi A1 pretreatment reversed the protection of miR-126 mimics against ox-LDL-induced HUVECs injury. Finally, our results showed that miR-126 mimics rescued ox-LDL-induced impaired autophagy flux through inhibiting PI3K/Akt/mTOR signaling. Taken together, our findings suggested that miR-126 alleviates ox-LDL-induced HUVECs injury through restoring autophagy flux via repressing PI3K/Akt/mTOR pathway, and further implicate the potential therapeutic targets to reverse atherosclerosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Inhibition of Notch signaling pathway using γ-secretase inhibitor delivered by a low dose of Triton-X100 in cultured oral cancer cells

Highlights: • A novel method is developed to deliver γ-secretase inhibitor DAPT using a low dose of Triton-X100. • This approach effectively blocks the cleavage of Notch1 receptor. • The elimination of Notch1 intracellular domain from cell nuclei is confirmed. • Notch1 signaling blockade in mRNA level is demonstrated upon applying this delivery system. How to effectively delivering therapeutic agents, including γ-secretase inhibitors (GSIs), into live cells, remains a significant challenge. This study assessed the effect of Notch signaling inhibition by examining levels of the Notch1 intracellular domain (N1ICD) in cultured oral cancer cells analyzed with random stitched images (2D) and 3D visualizations using confocal microscopy and quantitative gene analysis. Substantially, we have developed a novel method to assist the delivery of γ-secretase inhibitor, DAPT, into live cells in the presence of an effective minimum concentration of Triton-X100 (0.001%) without damaging cell activity and membrane integrity assessed with cell proliferation assays. The images obtained in this study showed that DAPT alone could not block the γ-secretase inhibitor despite inhibiting cell growth. Further analysis of quantitative gene expressions of Notch signaling canonical pathway to verify the effectiveness of the novel method for delivering inhibitor into live cells, displayed deregulation of Notch1, Delta-like ligand 1 (DLL1) and hairy and enhancer of split 1 (Hes1). Our data suggest that Notch1/Hes1 signaling pathway is deactivated using DAPT with a low dose of Triton-X100 in this cancer cells. And the finding also suggests that Notch1 could be engaged by DLL1 to promote differentiation in oral cancer cells. Using this approach, we demonstrate that Triton-X100 is a promising and effective permeabilization agent to deliver γ-secretase inhibitor DAPT into live oral epithelial cells. This strategy has the potential to implicate in the treatment of cancer diseases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

MiR-449 overexpression inhibits osteogenic differentiation of bone marrow mesenchymal stem cells via suppressing Sirt1/Fra-1 pathway in high glucose and free fatty acids microenvironment

Highlights: • MiR-449 expression was up-regulated during osteogenic differentiation. • MiR-449 mediates osteogenic differentiation of HG-FFA-treated hBMSCs. • MiR-449 directly targets Sirt1 by binding to its 3′-UTR. • MiR-449 regulates osteogenic differentiation via suppressing Sirt1/Fra-1 pathway. Diabetic osteoporosis is a chronic complication caused by diabetes mellitus, and However, the exact mechanism of diabetes mellitus-induced osteoporosis is still unknown. In this study, we investigate the effect of miR-449 on osteogenic differentiation and its underlying mechanism in human bone marrow-derived mesenchymal stem cells (hBMSCs) with high glucose (HG) and free fatty acids (FFA) treatment. Results showed that after culturing for 14 days, high glucose (HG) and free fatty acids (FFA) treatment dramatically decreased mineralization of human bone marrow-derived mesenchymal stem cells (hBMSCs) compared with cells treated with osteogenic medium (OM) alone. We also found that miR-449 expression was up-regulated during osteogenic differentiation of hBMSCs with HG and FFA treatment. Moreover, during osteogenic differentiation of hBMSCs with HG and FFA treatment, miR-449 mimics notably decreased the alkaline phosphatase (ALP) activity and the mRNA and protein expression levels of runt-related transcription factor 2 (Runx2), ALP, collagen I, osteocalcin (OCN), and bone sialoprotein (BSP), which was remarkably increased by miR-449 inhibitors. Furthermore, miR-449 directly targets Sirt1 by binding to its 3′-UTR. Sirt1 overexpression reverses the suppressive effect of miR-449 mimics on Fra-1 mRNA and protein expression, which was also alleviated by Fra-1 overexpression. In addition, Fra-1 overexpression alleviates the inhibitory effect of miR-449 mimics on the ALP activity and the mRNA and protein of Runx2, collagen I, OCN and BSP. Taken together, our results indicated that miR-449 overexpression inhibited osteogenic differentiation of HG-FFA-treated hBMSCs through the Sirt1/Fra-1 signal pathway. It is conceivable that modulating miR-449 might provide a new therapy for intervention in diabetic osteoporosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Multiple myeloma cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-β/Smad pathway activation

Highlights: • Hypoxia-adapted multiple myeloma cells exhibit stem cell characteristics. • Hypoxia-adapted multiple myeloma cells show higher tumorigenicity in vivo. • TGF-β/Smad pathway is critical for self-renewal for hypoxia-adapted myeloma cells. The emergence of new molecular targeting agents has improved the prognosis of patients with multiple myeloma (MM). However, MM remains incurable because MM stem cells are likely resistant to these agents. Thus, it is important to further investigate the biology of MM stem cells, which reside in the hypoxic bone marrow niche. In this study, we established and investigated the characteristics of hypoxia-adapted MM (HA-MM) cells, which could proliferate for more than six months under hypoxic conditions (1% O{sub 2}). The G0 fraction of HA-MM cells was larger than that of parental MM cells under normoxic conditions (20% O{sub 2}). HA-MM cells possess enhanced tumorigenicity in primary and secondary transplantation studies. HA-MM cells also exhibited increased mRNA levels of stem cell markers and an enhanced self-renewal ability, and thus demonstrated characteristics of MM stem cells. These cells overexpressed phosphorylated Smad2, and treatment with a transforming growth factor (TGF)-β/Smad signaling inhibitor decreased their clonogenicity in a replating assay. In conclusion, MM cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-β/Smad pathway activation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Curcumin protects cortical neurons against oxygen and glucose deprivation/reoxygenation injury through flotillin-1 and extracellular signal-regulated kinase1/2 pathway

Highlights: • Curcumin protects cortical neurons against OGD/R injury. • Curcumin regulates ERK and JNK phosphorylation in neurons under OGD/R. • Curcumin protects neurons against OGD/R injury via flotillin-1 and ERK1/2. In this study, we provided evidence that curcumin could be a promising therapeutic agent for ischemic stroke by activating neuroprotective signaling pathways. Post oxygen and glucose deprivation/reoxygenation (OGD/R), primary mouse cortical neurons treated with curcumin exhibited a significant decrease in cell death, LDH release and enzyme caspase-3 activity under OGD/R circumstances, which were abolished by flotillin-1 downregulation or extracellular signal-regulated kinase (ERK) inhibitor. Moreover, flotillin-1 knockdown led to suppression of curcumin-mediated ERK phosphorylation under OGD/R condition. Based on these findings, we concluded that curcumin could confer neuroprotection against OGD/R injury through a novel flotillin-1 and ERK1/2 pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

TINCR facilitates non-small cell lung cancer progression through BRAF-activated MAPK pathway

Highlights: • TINCR facilitates NSCLC. • TINCR interacts with BRAF. • TINCR activates MAPK by BRAF. Long non-coding RNAs are critically involved in oncogenesis in various cancer types. Here we reported a novel lncRNA signature correlated with progression of non-small cell lung cancer (NSCLC). In particular, we identified elevated expression of terminal differentiation-induced noncoding RNA (TINCR) in human NSCLC samples, which were associated with enhanced migration, viability in NSCLC cells in vitro. Higher TINCR level was also correlated with poor survival. Furthermore, TINCR increased xenograft tumor growth in vivo mouse models. Mechanistic study demonstrated that TINCR can interact with BRAF to facilitate its kinase activity, thereby leading to activation of oncogenic mitogen-activated protein kinase (MAPK) pathway. These results suggested that TINCR upregulation may signal through the MAPK pathway to promote NSCLC tumorigenesis. Therefore, TINCR may serve as a potential prognostic marker and therapeutic target for NSCLC patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Ghrelin promotes human non-small cell lung cancer A549 cell proliferation through PI3K/Akt/mTOR/P70S6K and ERK signaling pathways

Highlights: • Ghrelin promotes A549 cells proliferation through binding to GHSR. • Ghrelin activates PI3K/Akt/mTOR/P70S6K and ERK signaling pathways. • PI3K/Akt/mTOR/P70S6K and ERK signaling mediates ghrelin-induced A549 cells proliferation. Ghrelin is a gastric acyl-peptide that plays an important role in cell proliferation. In the present study, we explored the role of ghrelin in A549 cell proliferation and the possible molecular mechanisms. We found that ghrelin promotes A549 cell proliferation, knockdown of the growth hormone secretagogue receptor (GHSR) attenuated A549 cell proliferation caused by ghrelin. Ghrelin induced the rapid phosphorylation of phosphatidylinositol 3-kinase (PI3K), Akt, ERK, mammalian target of rapamycin (mTOR) and P70S6K. PI3K inhibitor (LY 294002), ERK inhibitor (PD98059) and mTOR inhibitor (Rapamycin) inhibited ghrelin-induced A549 cell proliferation. Moreover, GHSR siRNA inhibited phosphorylation of PI3K, Akt, ERK, mTOR and P70S6K induced by ghrelin. Akt and mTOR/P70S6K phosphorylation was inhibited by LY 294002 but not by PD98059. These results indicate that ghrelin promotes A549 cell proliferation via GHSR-dependent PI3K/Akt/mTOR/P70S6K and ERK signaling pathways.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Enterococcus faecalis lipoteichoic acid regulates macrophages autophagy via PI3K/Akt/mTOR pathway

Highlights: • We established RAW264.7 expressing mRFP-GFP-LC3 to observe autophagy. • Our data shown Enterococcus faecalis LTA activates macrophage autophagy via PI3K/Akt/mTOR pathway. • Beclin1 is necessary in LTA-stimulated autophagy of macrophage. Enterococcus faecalis (E. faecalis) infection is considered an important etiological factor for the development of persistent apical periodontitis (PAP), but the exact mechanisms of autophagy between E. faecalis and immune cells remain unknown. In this study, we elucidated how E. faecalis lipoteichoic acid (LTA) is associated with macrophages autophagy. We found that E. faecalis LTA apparently activated macrophage autophagy with significant increase of autophagosomes and autophagy relative protein. Meanwhile, we noticed significantly decreasing expression of p-Akt and p-mTOR. However, these effect were absent in macrophages knockdown of Beclin1. In summary, these findings suggested E. faecalis LTA may increased macrophages autophagy via inhibiting PI3K/Akt/mTOR pathway and this process was Beclin1 dependent.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Long noncoding RNA lncARSR promotes hepatic lipogenesis via Akt/SREBP-1c pathway and contributes to the pathogenesis of nonalcoholic steatohepatitis

Highlights: • The expression of lncARSR increased in NAFLD patients and mouse model. • lncARSR modulated hepatic lipid accumulation in vivo and in vitro. • SREBP-1c mediated the effect of lncARSR on lipognesis in NASH. • lncARSR regulated SREBP-1c via PI3K/Akt pathway. Non-alcoholic fatty liver disease and steatohepatitis (NAFLD and NASH) account for the majority of liver disease in industrialized countries. However, the pathogenesis still unclear. Long non-coding RNAs (lncRNAs) has been reported to be involved in various pathophysiological processes. Here, we reported a novel role of lncARSR in hepatic lipogenesis in NAFLD. The expression of lncARSR was induced both in NAFLD patients and mouse model, as well as in hepatocytes treated with fatty acid. Moreover, overexpression of lncARSR enhanced while knockdown of lncARSR ameliorated hepatic lipid accumulation in vivo and in vitro. Furthermore, the expression of genes related to fatty acid synthesis and oxidation increased with lncARSR overexpression in vivo. Mechanistically, we identified that lncARSR regulated hepatic lipogenesis via upregulating SREBP-1c, the key regulatory molecule involved in lipogenesis. Knockdown of SREBP-1c by shRNA blocked the effect of lncARSR on lipogenesis. Furthermore, we demonstrated that lncARSR regulated SREBP-1c expression by PI3K/Akt pathway. In conclusion, our data indicated that lncARSR potentially contributes to the hepatic steatosis in NAFLD, which may be a new therapeutic target against NAFLD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Oncogenic MicroRNA-20a is downregulated by the HIF-1α/c-MYC pathway in IDH1 R132H-mutant glioma

Highlights: • MiR-20a is down-regulated in IDH1 R132H mutant-glioma. • IDH1 R132H mutation attenuates miR-20a expression via HIF-1α/c-MYC pathway. • The downregulated miR-20a contributes to the therapeutic sensitivity of IDH1 mutant gliomas. Mutations in the isocitrate dehydrogenase 1 (IDH1) gene have been identified as one of the earliest events in gliomagenesis, occurring in over 70% of low grade gliomas and are present in the vast majority of secondary glioblastoma (GBM) that develop from these low-grade lesions. The aim of this study was to investigate whether the IDH1 R132H mutation influences the expression of oncogenic miR-20a and shed light on the underlying molecular mechanisms. The findings of the current study demonstrate presence of the IDH1 R132H mutation in primary human glioblastoma cell lines with upregulated HIF-1α expression, downregulating c-MYC activity and resulting in a consequential decrease in miR-20a, which is responsible for cell proliferation and resistance to standard temozolomide treatment. Elucidating the mechanism of oncogenic miR-20a activity introduces its role among well-established signaling pathways (i.e. HIF/c-MYC) and may be a meaningful prognostic biomarker or target for novel therapies among patients with IDH1-mutant glioma.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

CDCA3 promotes cell proliferation by activating the NF-κB/cyclin D1 signaling pathway in colorectal cancer

Highlights: • CDCA3 is upregulated in CRC tissues and cell lines. • Knockdown of CDCA3 inhibits CRC progression in vitro. • CDCA3 activates the NF-κB signaling pathway by interacting with TRAF2 in CRC. • Overexpression of CDCA3 upregulates the NF-κB- related gene Cyclin D1. Cell division cycle associated 3 (CDCA3) is required for mitotic entry, and mediates the degradation of the inhibitory kinase Wee1. New evidence suggests CDCA3 plays a role in tumor promotion. However, little is known about the relevance of CDCA3 in colorectal cancer(CRC), especially in the regulation of NF-κB activity. In this study, we found that colorectal tumors significantly expressed more CDCA3 than non-cancer tissues. In addition, CDCA3 promoted CRC cell proliferation in vitro. Furthermore, downregulation of CDCA3 not only induced cell cycle arrest but also facilitated apoptosis. Mechanistically, CDCA3 activates the NF-κB signaling pathway by interacting with TRAF2 in CRC. Together, these results define a tumor-supportive role for CDCA3, which may also provide a new promising strategy for treating CRC.

60 APPLIED LIFE SCIENCES↗