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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 1,531 records · Page 85
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Gene expression profile of TLR7 signaling pathway in the liver of rhesus rotavirus-induced murine biliary atresia

Highlights: • The day 7 postinoculation was the crucial time of rhesus rotavirus-induced murine biliary atresia onset. • The expression of TLR7 and activation of TLR7 signaling pathway in liver were significant in BA mice. • The expression of TLR7 was increased as pups aged in normal control mice. • TLR7 knockdown repressed cellular proliferation and made cells more fragile in RRV infection. • The lack of TLR7 immunopositive cells in liver may, in part, participate in the neonates in the development of BA mice. To identify genes potentially involved in the pathogenesis of bile duct obstruction in biliary atresia (BA).

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Circular RNA circ-CBFB promotes proliferation and inhibits apoptosis in chronic lymphocytic leukemia through regulating miR-607/FZD3/Wnt/β-catenin pathway

Circular RNA (circRNA) belongs to the non-coding RNA family and is involved in various human cancers, such as lung cancer and colorectal cancer. Nevertheless, whether circRNA expression is related to chronic lymphocytic leukemia (CLL) progression remains largely unclear. In our study, we investigated the role of circ-CBFB in CLL. We found that circ-CBFB was markedly overexpressed in CLL cells compared to normal controls. Furthermore, we found that circ-CBFB could serve as a diagnostic and prognostic biomarker for CLL patients. We also explored the physiological function of circ-CBFB. We found that circ-CBFB knockdown significantly suppressed CLL cell proliferation, arrested cell cycle progression, and induced cellular apoptosis. In terms of its mechanism, we identified circ-CBFB as a sponge of miR-607, which targeted FZD3. By inhibiting miR-607 availability, circ-CBFB promoted FZD3 expression, leading to the activation of the Wnt/β-catenin pathway and consequent CLL progression. Taken together, our findings revealed that the circ-CBFB/miR-607/FZD3/Wnt/β-catenin regulatory signaling cascade contributes to CLL progression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The role of uric acid in the pathogenesis of diabetic retinopathy based on Notch pathway

Uric acid has been proposed as an independent risk factor of diabetic retinopathy. Although Notch signaling was reported to be affected in the presence of high concentrations of uric acid or glucose, the underlying mechanisms of hyperuricemia through the Notch signaling pathway to promote the development of diabetic retinopathy remain unknown.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Regulation of the regulator of G protein signaling 2 expression and cellular localization by PKA and PKC pathways in mouse granulosa cells

G protein-coupled receptor (GPCR) activation-mediated PKA and PKC pathways have been recognized to be important in ovarian physiology. Expression of regulator of G-protein signaling 2 (RGS2) has been reported in ovarian granulosa cells. The detailed mechanisms in PKA- and PKC-regulated RGS2 expression and cellular translocation in granulosa cells remain mostly unclear. PKA activator 8-bromo-cAMP and PKC activator phorbol-12, 13-didecanoate appeared to rapidly elevate both protein and mRNA levels and promoter activation of RGS2 gene. Two consensus Sp1 elements within the shortest 78 bp fragment of RGS2 promoter sequence were essential for the full responsiveness to PKA and PKC. PKC activation appeared to increase the RGS2 translocation from nucleus to cytosol. PKA- and PKC-mediated RGS2 transcription in a Sp-1-dependent manner and a PKC-mediated RGS2 intracellular translocation were noted in granulosa cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Inhibition of microRNA-16 facilitates the paclitaxel resistance by targeting IKBKB via NF-κB signaling pathway in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a common malignant tumor usually resistant to chemotherapy. MicroRNAs play important roles in modulation of carcinogenesis and chemoresistance, which miR-16 has been reported to mediate chemoresistance in many types of cancers. However, the role of miR-16 in HCC remains unknown. The aim of this study was to investigate whether miR-16 is participated in chemoresistance in HCC and shed light on the underlying molecular mechanisms. The findings of the current study discover that miR-16 is down-regulated in HCC tissue and cell lines. The results demonstrate that the inhibition of miR-16 renders resistance to paclitaxel in vitro and in vivo by targeting IKBKB via NF-κB signaling pathway, suggesting that miR-16 may be a meaningful therapeutic potential to overcome drug resistance in HCC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

MagT1 is essential for Drosophila development through the shaping of Wingless and Decapentaplegic signaling pathways

Magnesium transporter subtype 1 (MagT1) is a magnesium membrane transporter with channel like properties. We have previously identified MagT1 (CG7830) in Drosophila genome and characterized its protein product by electrophysiological means. Here, we report the generation of fly MagT1 mutants and show that MagT1 is essential for early embryonic development. In wings and primordial wings, by clonal analysis and RNAi knock down of MagT1, we have found that loss of MagT1 results in enhanced/ectopic Wingless (Wg, a fly Wnt) signaling and disrupted Decapentaplegic (Dpp) signaling, indicating the crucial role of MagT1 for fly development at later stages. Finally, we demonstrate directly that magnesium transportations are proportional with the MagT1 expressional levels in Drosophila S2 cells. Taken together, these findings may suggest that MagT1 is a major magnesium transporter/channel profoundly involved in fly development by affecting developmental signaling pathways, such as Wg and Dpp signaling.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

miR-410–3p promotes prostate cancer progression via regulating PTEN/AKT/mTOR signaling pathway

Prostate cancer has become one of commonest urologic tumors in male. In recent years, miRNAs are continually attracting attentions of researchers for their special regulatory function in human cancers. Previous study has revealed that miR-410 acts as a biomarker for the diagnosis of prostate cancer. Whereas, the specific biological function of miR-410–3p in prostate cancer remains unknown. The aim of this study is to explore the function and molecular mechanism of miR-410–3p in prostate cancer. The high expression of miR-410–3p was examined in prostate cancer tissues and cell lines by qRT-PCR. Next, the prognostic value was identified by Kaplan Meier method. High expression of miR-410–3p indicated poor prognosis of prostate cancer patients. To investigate the biological function of miR-410–3p in prostate cancer, loss-of function assays were designed and performed in two prostate cancer cell lines (PC3 and DU145). As a result, downregulated miR-410–3p suppressed cell proliferation, migration and EMT progress. Moreover, flow cytometry analysis was performed to determine that the acceleration effects of miR-410–3p on cell apoptosis. Mechanistically, further analysis demonstrated that the effects of miR-410–3p exert oncogenic functions through downregulating PTEN. All findings in this study revealed that miR-410–3p inhibits prostate cancer progression via downregulating PTEN/AKT/mTOR signaling pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

HDAC9 promotes brain ischemic injury by provoking IκBα/NF-κB and MAPKs signaling pathways

Highlights: • HDAC9 deletion protects against I/R-induced ischemic brain injury in vivo. • HDAC9 ablation down-regulates I/R-induced inflammation in brain of mice. • HDAC9 knockdown alleviates LPS-induced inflammation in BV2 cells partially by MAPKs pathway. Ischemic stroke is an acute cerebrovascular disease due to poor blood flow to the brain. Nevertheless, there is still no effective therapy for it and the pathology contributing to ischemic stroke is not fully understood. Histone Deacetylase 9 (HDAC9) is a class IIa chromatin-modifying enzyme. HDAC9 gene region is a leading risk locus for large artery atherosclerotic stroke. However, the mechanisms linking HDAC9 to ischemic remain elusive. In the study, we attempted to explore HDAC9-associated inflammatory response using the wild type (WT) and HDAC9-knockout (KO) mice with brain ischemic injury. The results indicated that WT mice with ischemia brain exhibited higher expression levels of HDAC9. HDAC9 depletion resulted in a decreased infarct volume and an improved neurological function in mice after ischemic reperfusion (I/R) injury. I/R injury markedly enhanced GFAP and Iba-1 expressions in cortex and HDAC9 knockout significantly reversed this up-regulation. Loss of HDAC9 inhibited the release of inducible NO-synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin 1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and IL-18 in cortex, hippocampus and hypothalamus of mice with I/R injury, which occurred at the transcription levels. Furthermore, the inhibitory actions of HDAC9 deficiency were associated with the down-regulation of phosphorylated-IκBα, phosphorylated-nuclear factor-kappa B (NF-κB), and p-mitogen-activated protein kinases (MAPKs), including phosphorylated-p38, phosphorylated-extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphorylated-c-Jun N-terminal kinase (JNK). Importantly, the in vitro study indicated that HDAC9 inhibition-reduced inflammation and activation of IκBα/NF-κB were restored by promoting MAPKs activity in LPS-stimulated cells. Our findings suggest that HDAC9 inhibition showed neuroprotective effects on ischemic stroke by restraining inflammation, which might help develop new and effective strategies for the therapeutic interventions in ischemic stroke.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

TLR4 mediates high-fat diet induced physiological changes in mice via attenuating PPARγ/ABCG1 signaling pathway

High-fat diet (HFD) is known to promote atherosclerosis which accelerates the development of atherosclerotic cardiovascular diseases. Vascular dysfunction characterized by inflammation and lipid accumulation is common in atherosclerosis caused by HFD. The specific effects of HFD on blood vessels and the underlying mechanisms need to be further clarified. Toll-like receptor 4 (TLR4) is a key contributing factor in atherosclerosis and TLR4 deficiency protects vascular smooth muscle cells against inflammatory responses and lipid accumulation in vitro. However, the physiological significance of TLR4 signaling in HFD-induced changes is unknown. In this study, we observed that HFD feeding increased body weight, circulating inflammatory cytokines and lipid accumulation in the aorta of wild-type mice but apart from increasing body weight, did not affect the TLR4 knockout mice. TLR4 expression increased significantly in the arterial walls after receiving HFD treatment, while that of the co-localizing PPARγ and ABCG1 markedly decreased. TLR4 deficiency reversed the HFD-induced attenuation of PPARγ and ABCG1. In conclusion, TLR4 mediates HFD induced increase in body weight, inflammation and aortic lipid accumulation through, at least partly, the PPARγ/ABCG1 signaling pathway. Therefore, interfering with TLR4 signaling is a viable therapeutic option in diet induced atherosclerosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

ANGPTL2 deletion inhibits osteoclast generation by modulating NF-κB/MAPKs/Cyclin pathways

Highlights: • ANGPTL2 is associated with the osteoclast development. • Inhibition of ANGPTL2 reduces the proliferation of osteoclast precursors. • ANGPTL2 deficiency alleviates ovariectomy (OVX)-induced bone loss. Osteoclasts are multinucleated cells essential for bone-resorption. Successful repair of bone defciencies still remains a great challenge worldwide. The signaling factor angiopoietin-like protein 2 (ANGPTL2), one of eight ANGPTL proteins, functions in maintenance of tissue homeostasis partly through regulating inflammation. In the study, ANGPTL2 expression was promoted during osteoclast development and that suppressing ANGPTL2 alleviated osteoclast production regulated by macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL). The results suggested that ANGPTL2 knockdown inhibited M-CSF-caused proliferation of osteoclast precursor cells. Further, ANGPTL2 silence reduced nuclear factor of activated T cell c 1 (NFATC1) and NFATC4 expressions in M-CSF-treated cells, along with decreased Runx2, OPN and Colla1. Moreover, silencing ANGPTL2 down-regulated M-CSF-promoted expressions of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and chemoattractant protein-1 (CCL-2). Consistently, ANGPTL2 knockdown reduced M-CSF-enhanced activation of IKKα, IκBα and nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPKs) (p38 MAPK, ERK1/2 MAPK and JNK MAPK). Additionally, knockdown of ANGPTL2 inhibited the induction of Cyclin D1, Cyclin D2 and Cyclin E1 due to M-CSF exposure. In vivo, we confirmed that ANGPTL2 knockout (KO) mice were protected against osteoporosis induced by ovariectomy (OVX), as proved by the improved bone loss and bone mineral density (BMD). Decreased expression of NFATCs was also observed in OVX-induced mice in the absence of ANGPTL2. Elevated release of pro-inflammatory cytokines was abrogated by ANGPTL2 knockout in femoral heads of mice with OVX operation, accompanied with a significant reduction of phosphorylated NF-κB and MAPKs signaling pathways. And down-regulated expression of Cyclin D1, Cyclin D2 and Cyclin E1 was observed in OVX-operated mice with ANGPTL2 knockout. Therefore, our study indicated that ANGPTL2 played an essential role in osteoclast generation through regulating the proliferation and inflammation of osteoclast lineage cells, providing new insights into the therapeutic strategy to alleviate bone loss.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

miR-5590-3p inhibited tumor growth in gastric cancer by targeting DDX5/AKT/m-TOR pathway

Recent evidence suggests that microRNAs play important roles in the negative post-transcriptional regulators with altered expression levels found in gastric cancer (GC). Therefore, we employed explore the anti-cancer miRNA and the potential mechanisms by which miRNAs modulate GC progression. We have predicted GC miRNA expression data sets in TargetScan. miR-5590-3p is higher in adjacent nonmalignant tissue than in cancer tissue in 42 pairs of GC tissues. Functional assays, CCK-8 and colony formation assay, were used to determine the Anti-cancer role of miR-5590-3p in human GC progression. In addition, Ago2-based RIP and dual-luciferase reporter assay were conducted to study the miR-5590-3p as a direct target of DDX5. Next, Xenograft nude mouse models were used to determine the role of miR-5590-3p in GC tumorigenicity in vivo. Upregulation of miR-5590-3p suppressed GC cell proliferation, whereas downregulation of miR-5590-3p promoted GC proliferation in vitro. Furthermore, we identified DDX5 as a direct target of miR-5590-3p, and that the biological function of miR-5590-3p during GC progression in vitro and in vivo is through the DDX5/AKT/m-TOR pathway and downstream cyclinD1 and CDK2 expression. Finally, we confirmed the effect of miR-5590-3p directly targeting DDX5 on the development of gastric cancer through salvage experiments in vivo and in vitro.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Interleukin-22 promotes triple negative breast cancer cells migration and paclitaxel resistance through JAK-STAT3/MAPKs/AKT signaling pathways

Highlights: • The “only IL-22” producing (Th22) cells were gradually increased in normal, paratumor and tumor tissues of TNBC patients. • IL-22 promotes TNBC cells (MDA-MB 231 and MDA-MB 468) migration and induces paclitaxel resistance. • IL-22 induces TNBC cells migration and paclitaxel resistance through JAK-STAT3/MAKPs/AKT signaling pathways. Owing to the absence of any targeted therapies, triple negative breast cancer (TNBC), which accounts for approximately 15% of all breast cancers, typically have a poorer outcome. In an attempt to find out the TNBCs' microenvironment, we ran into the endogenous expression of a newly discovered cytokine known as Interleukin (IL)-22.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Saxagliptin regulates M1/M2 macrophage polarization via CaMKKβ/AMPK pathway to attenuate NAFLD

Highlights: • The anti-inflammatory effect of DPP-4 inhibitor saxagliptin against NAFLD is proposed beyond its hypoglycemic effect. • The polarization of M1/M2 macrophage is involved in anti-inflammatory mechanism of saxagliptin. • This mechanism may be via CaMKKβ-dependent AMPK activation. Non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic disease, is an important complication of diabetes mellitus (DM). Inflammation plays a crucial role in the development and progression of NAFLD. Moreover, the pathological formation of NAFLD is closely related to accumulation and polarization of hepatic macrophages. Saxagliptin, a newly antidiabetic agent, can suppress hepatic inflammation reportedly. However, underlying mechanisms remain poorly explored. In this study, we showed saxagliptin alleviated lipid accumulation and attenuated liver inflammation with downregulation of inflammation factors in diabetic rats. Moreover, saxagliptin could reduce the phenotype of M1 macrophage iNOS and increase the phenotype of M2 macrophage CD206. We also found saxagliptin increased CaMKKβ/AMPK activation. In vitro, human THP-1 monocytes were differentiated into M1/M2 macrophages by LPS/IL-4. We clarified saxagliptin's anti-inflammatory effect by reducing NF-κB, TNF-α expression and promoting M2 macrophage polarization. Furthermore, we demonstrated CaMKKβ-dependent AMPK activation was involved in macrophage polarization. In conclude, our results detected saxagliptin could attenuated inflammation through regulation of M1/M2 macrophage polarization and might be via CaMKKβ/AMPK pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The LncRNA MALAT1 regulates CD80 transcription via the NF-κB signaling pathway in the A549 cell line

CD80 has been known to be a co-stimulatory factor expressed in antigen presenting cells (APCs) involved in T-cell activation. It can be expressed in non-bone marrow-derived cells induced by lipopolysaccharide (LPS) or other stimulators, and directly involved in the pathogenesis following T cell activation. However, the intricate transcription mechanisms that underlying the upregulation of CD80 expression levels in LPS-activated non-bone marrow-derived cells is still unknown. LncRNAs are confirmed to be involved in transcriptional regulation by influencing transcription factors. Therefore, we wanted to determine whether the lncRNA MALAT1, which has been found to be related to LPS-induced inflammation, could regulate the transcription of CD80. Our results showed that CD80 was upregulated in low-dose LPS-activated A549 cells in a NF-κB-dependent manner. The lncRNA MALAT1 can interfere with NF-κB activation and disrupt its binding efficiency with the CD80 promoter. Thus, the lncRNA MALAT1 can regulate CD80 transcription via the NF-κB signaling pathway in the LPS-activated A549 cell line.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Long noncoding RNA LUCAT1 promotes malignancy of ovarian cancer through regulation of miR-612/HOXA13 pathway

Emerging evidence shows that long noncoding RNA (lncRNA) is implicated in numerous kinds of malignant cancers, including ovarian cancer. In this study, we focused on the expression and function of long noncoding RNA lung cancer associated transcript 1 (LUCAT1) in ovarian cancer progression. We indicated that LUCAT1 expression was significantly upregulated in ovarian cancer tissues. Moreover, LUCAT1 expression was positively associated with tumor metastasis and clinical stage. Elevated expression of LUCAT1 decreased the survival rate of patients with ovarian cancer. In addition, we revealed that repression of LUCAT1 significantly suppressed the proliferation, migration and invasion, whereas promoted apoptotic rate. Through online predictive tools and functional experiments, we demonstrated that LUCAT1 and HOXA13 were targets of miR-612. We showed that LUCAT1 and miR-612 suppressed each other in a reciprocal way. Moreover, LUCAT1 promoted HOXA13 expression through inhibition of miR-612, eventually leading to ovarian cancer development. In conclusion, our findings revealed a novel molecular mechanism that LUCAT1/miR-612/HOXA13 pathway modulates ovarian cancer progression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

ZIC5 facilitates the growth of hepatocellular carcinoma through activating Wnt/β-catenin pathway

Highlights: • High ZIC5 expression in specimens indicates poor prognosis of HCC patients. • ZIC5 was required in proliferation and tumorigenicity of HCC. • ZIC5 promotes proliferation and tumorigenicity of HCC cells. • ZIC5 promoted growth of HCC in a β-catenin dependant manner. The incidence and mortality of hepatocellular carcinoma (HCC) is high, but the mechanisms underlying the growth and progression of HCC have not been elucidated. Recently, the ZIC family member 5 (ZIC5) is emerging as an oncogene in various types of tumors. However, its expression and biological role in HCC have not been reported. This study first demonstrated that ZIC5 was up-regulated in HCC specimens, and high ZIC5 expression indicated poor prognosis of HCC patients. In addition, over-expressed ZIC5 promoted the proliferation, migration and invasion of HCC cell lines Huh7 and HepG2 in vitro and in vivo, while ZIC5 knockdown achieved the opposite effects. Actually, ZIC5 increased the expression of genes participating in Wnt/β-catenin pathway such as β-catenin and CyclinD1. ZIC5 also promoted β-catenin to enter the nucleus of HCC cells. Furthermore, silencing β-catenin abated the promoting role of ZIC5 in HCC. Overall, this study reveals a novel mechanism of ZIC5/β-catenin that mediates the invasion and metastasis of HCC and ZIC5 serves as a novel indicator for prognosis of HCC patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Resistin destroys mitochondrial biogenesis by inhibiting the PGC-1α/ NRF1/TFAM signaling pathway

Highlights: • Resistin caused impairment of mitochondrial biogenesis in neuronal cells. • Resistin induced loss of mitochondrial function by reducing respiration rate and ATP. • Resistin inhibited the PGC-1α/NRF1/TFAM pathway. • PGC-1α abolished the inhibitory effects of resistin in mitochondrial biogenesis. Mitochondrial biogenesis deficits in neuronal cells are associated with the pathological progression of neurodegenerative diseases. Resistin, a secretory adipocytokine, possesses multiple physiological functions in diverse cells and tissues. However, the effects of resistin on mitochondrial biogenesis in neuronal cells are still elusive. In the current study, we found that resistin caused a sustainable decrease in mitochondrial contents, including mitochondrial DNA/nuclear DNA ratio (mtDNA/nDNA), mitochondrial mass, cytochrome b protein expression, and cytochrome c oxidase activity, which were correlated with “loss of mitochondrial function” including reduced mitochondrial respiration rate and ATP production in human SH-SY5Y neuronal cells. Indeed, resistin treatment destroyed the expression of peroxisome proliferator activator receptor gamma-coactivator 1α (PGC-1α), a master regulator of mitochondrial biogenesis, as well as its downstream target genes including nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM). Notably, overexpression of PGC-1α could completely rescue mitochondrial biogenesis and mitochondrial deficits induced by resistin. Mechanistically, inhibition of 5′-adenosine monophosphate-activated protein kinase (AMPK) was shown to mediate the inhibitory effects of resistin on mitochondrial biogenesis.

60 APPLIED LIFE SCIENCES↗