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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 1,477 records · Page 82
All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

Modulation of hepatic stellate cells and reversibility of hepatic fibrosis

Hepatic fibrosis (HF) is the pathological component of a variety of chronic liver diseases. Hepatic stellate cells (HSC) are the main collagen-producing cells in the liver and their activation promotes HF. If HSC activation and proliferation can be inhibited, HF occurrence and development can theoretically be reduced and even reversed. Over the past ten years, a number of studies have addressed this process, and here we present a review of HSC modulation and HF reversal. - Highlights: • We present a review of the modulation of hepatic stellate cells (HSC) and reversibility of hepatic fibrosis (HF). • HSC are the foci of HF occurrence and development, HF could be prevented and treated by modulating HSC. • If HSC activation and proliferation can be inhibited, HF could theoretically be inhibited and even reversed. • Prevention or reversal of HSC activation, or promotion of HSC apoptosis, immune elimination, and senescence may prevent, inhibit or reverse HF.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

The role of cardiac energy metabolism in cardiac hypertrophy and failure

In mammalian heart, incessant production of cellular energy is vital for maintaining continuous mechanical pumping function providing the body for oxygen and nutrients. To ensure this essential function, cardiac muscle adapt to increased energy demand or compromised energy supply by reprogramming the network of genes whose products are necessary to match the production of energy to consumption. Failure in this regulation leads to severe cardiac dysfunction and has been associated with cardiac pathogenesis including cardiac hypertrophy, failure and diabetes. Metabolic adaptations are induced by network of transcriptional pathways that are activated by a variety of factors such as hormones, nutrients, second messengers and oxygen. The metabolic phenotype of the heart is maintained by pathways controlling transcriptional regulators, which include peroxisome proliferator-activated receptors, estrogen-related receptors and nuclear respiratory factors, as well as their common coactivator protein peroxisome proliferator-activated receptor γ coactivator 1. These central regulators of gene expression are complemented with factors such as hypoxia inducible factor 1, which is activated in insufficient oxygenation of the tissue. Here, we discuss how these pathways relate to the cardiac metabolism and how they interact with pathways controlling the contractile phenotype of the heart. - Highlights: • Energy metabolic changes are associated with cardiac adaptation and pathogenesis. • Cardiac energy substrate utilisation is controlled by complex transcriptional networks. • Transcriptional pathways controlling heart metabolic and contractile phenotype overlap.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

miR-429 inhibits metastasis by targeting KIAA0101 in Soft Tissue Sarcoma

Soft tissue sarcomas (STS) are a heterogeneous group of rare tumors with high metastatic potential. There being only a handful of publication on metastasis of STS, we investigated the miRNA mediated target gene regulations in modulating the metastatic processes in this cancer. In this study, we amalgamated gene and miRNA expression profiles of high-grade STS samples with miRNA target predictions and identified miR-429 targeting KIAA0101 as a novel pair, which remain unexplored in STS metastasis. We validated their expression in metastatic fibrosarcoma cell line, HT1080 and performed several functional assays using miRNA mimics and KIAA0101 over-expression vector to confirm their role in metastasis. We observed miR-429 is downregulated in HT1080 cells and acting as an anti-metastatic miRNA that inhibited proliferation, migration, anchorage independent growth and invasion by de-repressing KIAA0101. Moreover, the renilla luciferase reporter assay confirmed that miR-429 targets KIAA0101 by binding to its 3{sup /}UTR and influence its expression. Taken together, our work demonstrated miR-429 mediates deregulation of KIAA0101 by acting as an anti-metastatic miRNA that targets KIAA0101 pro-metastatic gene during metastasis of STS. - Highlights: • miR-429 inhibits metastasis by targeting KIAA0101 in Soft Tissue Sarcoma. • miR-429 suppresses proliferation, migration, anchorage independent growth and invasion in HT1080. • We validated targeting of miR-429 and KIAA0101 by reporter assay. • KIAA0101 overexpression is involved in decreased survival of STS patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Function and regulation of LAG3 on CD4{sup +}CD25{sup -} T cells in non-small cell lung cancer

LAG3 is a surface molecule found on a subset of immune cells. The precise function of LAG3 appears to be context-dependent. In this study, we investigated the effect of LAG3 on CD4{sup +}CD25{sup -} T cells from non-small cell lung cancer (NSCLC) patients. We found that in the peripheral blood mononuclear cells of NSCLC patients, LAG3 was significantly increased in CD4{sup +} T cells directly ex vivo and primarily in the CD4{sup +}CD25{sup -} fraction, which was regulated by prolonged TCR stimulation and the presence of IL-27. TCR stimulation also increased CD25 expression, but not Foxp3 expression, in LAG3-expressing CD4{sup +}CD25{sup -} cells Compared to LAG3-nonexpressing CD4{sup +}CD25{sup -} cells, LAG3-expressing CD4{sup +}CD25{sup -} cells presented significantly higher levels of PD1 and TIM3, two inhibitory receptors best described in exhausted CD8{sup +} T effector cells. LAG3-expressing CD4{sup +}CD25{sup -} cells also presented impaired proliferation compared with LAG3-nonexpressing CD4{sup +}CD25{sup -} cells but could be partially rescued by inhibiting both PD1 and TIM3. Interestingly, CD8{sup +} T cells co-incubated with LAG3-expressing CD4{sup +}CD25{sup -} cells at equal cell numbers demonstrated significantly lower proliferation than CD8{sup +} T cells incubated alone. Co-culture with CD8{sup +} T cell and LAG3-expressing CD4{sup +}CD25{sup -} T cell also upregulated soluble IL-10 level in the supernatant, of which the concentration was positively correlated with the number of LAG3-expressing CD4{sup +}CD25{sup -} T cells. In addition, we found that LAG3-expressing CD4{sup +}CD25{sup -} T cells infiltrated the resected tumors and were present at higher frequencies of in metastases than in primary tumors. Taken together, these data suggest that LAG3-expressing CD4{sup +}CD25{sup -} T cells represent another regulatory immune cell type with potential to interfere with anti-tumor immunity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

1,25(OH)2D3 attenuates pulmonary arterial hypertension via microRNA-204 mediated Tgfbr2/Smad signaling

Highlights: • miRNA-204 is significantly lower in hypoxic pulmonary hypertension. • miRNA-204 is involved in the development of pulmonary hypertension. • 1,25(OH){sub 2}D{sub 3} significantly prevented the development of PAH by blocking the Tgfbr2/Smad signaling. • 1,25(OH){sub 2}D{sub 3} reduced pulmonary hypertension mediated by increased the level of miRNA-204. • miRNA-204 strengthened the anti-PAH function of 1,25(OH){sub 2}D{sub 3} by targeting Tgfbr2. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by high pulmonary artery pressure. It is reported that microRNA-204 (miR-204) plays an important role in the development of PAH. Calcitriol [1,25-dihydroxyvitamin D3, 1,25(OH){sub 2}D{sub 3}] mediates multiple pathophysiological processes. The aim of the current study was to explore the role of 1,25(OH){sub 2}D{sub 3} in PAH. PAH was induced in rats and rat pulmonary arterial endothelial cells (PAECs) were isolated as in vitro PAH model. The mean pulmonary artery pressure, morphologic changes, and expressions of transforming growth factor-beta1 (Tgfbr2), Smad2/7, alpha smooth muscle actin (α-SMA), and p21 were then measured. Furthermore, the effect of 1,25(OH){sub 2}D{sub 3} on rat PAECs with or without hypoxia treatment was also assessed by measuring the proliferation, migration, and cell cycle distribution of PAECs. The potential targets of miR-204 were also predicted and validated with a dual-luciferase reporter system. Then the role of miR-204 and Tgfbr2 in the anti-PAH effect of 1,25(OH){sub 2}D{sub 3} was further explored by modulating the expression of the two genes. The overall pulmonary hypertension and hypoxia-induced proliferation and migration of PAECs were attenuated by administration of 1,25(OH){sub 2}D{sub 3}, which was associated with the suppressed expressions of Tgfbr2, α-SMA, and Smad7 and induced expressions of miR-204, p21 and Smad2 both in vitro and in vivo. Moreover, the luciferase reporter assay identified Tgfbr2 as a novel direct target of miR-204. Both overexpression of miR-204 and inhibition of Tgfbr2 would strengthen the effect of 1,25(OH){sub 2}D{sub 3} administration. Findings outlined in the current study demonstrated that 1,25(OH){sub 2}D{sub 3} was a promising therapeutic modality for treatment of PAH, function of which was exerted through miR-204 mediated Tgfbr2 signaling.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Potential role of MG53 in the regulation of transforming-growth-factor-β1-induced atrial fibrosis and vulnerability to atrial fibrillation

Highlights: • MG53 is expressed in human atrium and associated with AF. • MG53 could regulate TGF-β1/Smad pathway to induce atrial fibrosis. • Exogenous TGF-β1 suppresses expression of MG53. • MG53 could serve as a promising target agent for atrial fibrosis induced by the TGF-β1/Smad pathway in patients with AF. Atrial fibrosis plays a critical role in atrial fibrillation (AF) by the transforming growth factor (TGF)-β1/Smad pathway. The disordered differentiation, proliferation, migration and collagen deposition of atrial fibroblasts play significant roles in atrial fibrosis. Mitsugumin (MG)53 is predominantly expressed in myocardium of rodents and has multiple biological functions. However, the role of MG53 in cardiac fibrosis remains unclear. This study provided clinical and experimental evidence for the involvement of MG53 in atrial fibrosis in humans and atrial fibrosis phenotype in cultured rat atrial fibroblasts. In atrial tissue from patients we demonstrated that MG53 was expressed in human atrium. Expression of MG53 increased with the extent of atrial fibrosis, which could induce AF. In cultured atrial fibroblasts, depletion of MG53 by siRNA caused down-regulation of the TGF-β1/Smad pathway, while overexpression of MG53 by adenovirus up-regulated the pathway. MG53 regulated the proliferation and migration of atrial fibroblasts. Besides, exogenous TGF-β1 suppressed expression of MG53. In conclusion, we demonstrated that MG53 was expressed in human atrium, and may be a potential upstream of the TGF-β1/Smad pathway in human atrium and rat atrial fibroblasts. This suggests that MG53 is a potential regulator of atrial fibrosis induced by the TGF-β1/Smad pathway in patients with AF.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Abrogation of Fam20c altered cell behaviors and BMP signaling of immortalized dental mesenchymal cells

Highlights: • Fam20c deficiency decreases the proliferation, mobility and mineralization of mouse immortalized dental mesenchymal cells. • Fam20c deficiency decreases the tooth mineralization, as well as the gene expression on dental mesenchymal differentiation. • Canonical and non-canonical BMP signaling pathways are declined in the mouse Fam20c-deficient dental mesenchyaml cell line. FAM20C mutations compromise the mineralization of skeleton and tooth in both human and mouse. Putatively, the mineralization disorder is attributed to the elevated fibroblast growth factor 23 (FGF23), which reduced the serum phosphorus by suppressing the reabsorption of phosphorus in kidney. Besides the regulation on systemic phosphorus homeostasis, FAM20C was also implicated to regulate cell behaviors and gene expression through a cell-autonomous manner. To identify the primary effects of Fam20c on dental mesenchymal cells, mouse Fam20c-deficient dental mesenchymal cells were generated by removing the floxed alleles from the immortalized mouse Fam20c{sup f/f} dental mesenchymal cells with Cre-expressing lentivirus. The removal of Fam20c exerted no impact on cell morphology, but suppressed the proliferation and mobility of the dental mesenchymal cells. Fam20c deficiency also significantly reduced the expression of Osterix, Runx2, type I Collagen a 1 (Col1a1), Alkaline phosphatase (Alpl) and the members of the small integrin-binding ligand, N-linked glycoprotein (SIBLING) family, but increased Fgf23 expression. Consistently, the in vitro mineralization of Fam20c-deficient dental mesenchymal cells was severely disabled. However, supplements of the non-collagenous proteins from wild type rat dentin failed to rescue the compromised mineralization, suggesting that the roles of FAM20C in tooth mineralization are more than phosphorylating local matrices and regulating systemic phosphorus metabolism. Moreover, the down-regulated BMP signaling pathways in the Fam20c deficient dental mesenchymal cells revealed that the kinase activity of FAM20C might be required to maintain BMP signaling. In summary, our study discloses that Fam20c indeed regulates cell behaviors and cell signaling pathway in a cell-autonomous manner.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Silencing of Kangai 1 C-terminal interacting tetraspanin suppresses progression of cholangiocarcinoma

Highlights: • KITENIN is expressed in murine and human cholangiocarcinoma (CC). • Knockdown of KITENIN reduced proliferation, migration, invasion and colony formation in CC cells. • Silencing of KITENIN inhibited the expression of epithelial-mesenchymal transition markers. • Targeting of KITENIN might function as a new therapeutic strategy against CC. Cholangiocarcinoma (CC) is the second most common primary hepatic malignancy. CC treatment options are very limited especially for patients with distant metastasis. Kangai 1 C-terminal interacting tetraspanin (KITENIN) is highly expressed in numerous cancers, but the role of KITENIN in CC remains unknown. Here, we have investigated for the first time the function of KITENIN in human CC cell lines (TFK-1, SZ-1), tissues and a CC mouse model (Alb-Cre/LSL-KRAS{sup G12D}/p53{sup L/L}). KITENIN was expressed in 92.2% of human CC tissues, in murine CC samples and also in human CC cell lines. Knockdown of KITENIN by small interfering RNA (siRNA) effectively reduced proliferation, migration, invasion and colony formation in both intra- and extra-hepatic CC cells. The expression of epithelial-mesenchymal transition (EMT) markers like N-cadherin, Vimentin, Snail and Slug were suppressed in KITENIN knockdown CC cells. Our results indicate that KITENIN is crucial for cholangiocarcinogenesis and it might become a potential therapeutic target for human CC treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Survivin regulated by autophagy mediates hyperglycemia-induced vascular endothelial cell dysfunction

Highlights: • HG did not induce endothelial cell injury directly, but increased cell viability after 72 h. • HG triggered upregulation of survivin expression as well as key components of autophagy pathway. • Survivin regulated HG-induced vascular endothelial cell dysfunction mediated by autophagy pathway. Diabetic vascular complications are often defined by vascular endothelial lesions. However, as a plastic cell type, whether endothelial cells could transit from quiescence to hyper-active status and hamper vascular stability upon hyperglycemia stimulation and whether this process is involved in diabetic vascular complications remain obscure. Survivin has been identified as an anti-apoptotic protein in tumor or epithelial cells by either promoting proliferation or inhibiting apoptosis. Therefore, this study aims at investigating the effects of hyperglycemia on endothelial cell status and the potential involvement of survivin. We found that high glucose (25 mM) did not cause endothelial injuries, instead, it evidently promotes endothelial proliferation and tube formation capacity indicating endothelial cell dysfunction upon hyperglycemia characterized by its preference to hyper-active status. Concomitantly, an upregulation of survivin was detected accompanied by the key component elevations of autophagy pathway including LC3, Beclin1, and p62. YM155, a specific inhibitor of survivin, could abrogate hyperglycemia-induced endothelial hyper-activation. Application of the autophagy inhibitor (3MA) and agonist (rapamycin) supported that survivin could be as a downstream effect or of autophagy. Thus, our results suggested that survivin/autophagy axis a potential therapeutic target in treatment of diabetic vascular complications.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

ISG15 promotes esophageal squamous cell carcinoma tumorigenesis via c-MET/Fyn/β-catenin signaling pathway

Highlights: • ISG15 is highly expressed in ESCC tissues and plasma, representing a promising diagnostic marker. • ISG15 positively regulated the proliferation, invasion and migration in vitro and in vivo. • ISG15 mediates the tumorigenesis via c-MET/Fyn/β-catenin pathway. Esophageal squamous cell carcinoma (ESCC) is one of the most malignant tumors in China with a poor prognosis. Most ESCC patients were diagnosed at advanced stages, losing the opportunity for surgical excision. Hence, it remains a pressing work to identify biomarkers for early detection, prognosis prediction and targeting therapies in ESCC. Interferon-stimulated gene 15 (ISG15) encodes a 15-kDa protein, and is involved in the post-translational modification (PTMs) of multiple proteins. However, the molecular functions of ISG15 in ESCC remain unclear. In this work, we found that ISG15 was aberrantly expressed in ESCC tissues and cell lines. Enhanced protein level of ISG15 promoted cellular malignant phenotypes including proliferation, migration, invasion and tumor formation in vivo. Consistently, reduction of ISG15 attenuated the cellular malignant phenotype in ESCC cell lines. Furthermore, gene-expression profiles suggested that the differentially expressed ISG15 affected the expression of a panel of genes enriched in the cell adherens junction, such as c-MET. Notably, as a secreted protein, the concentration of ISG15 was elevated in ESCC plasma than healthy individuals, acting as a potential diagnostic marker. Taken together, our results suggested a tumor promotion role of ISG15 in ESCC via c-MET/Fyn/β-catenin pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Exosomes derived from endothelial progenitor cells ameliorate acute lung injury by transferring miR-126

Highlights: • Administration of EPC-Exos ameliorated LPS-induced ALI and restored the in vivo lung integrity. • The microRNA miR-126 was enriched in EPC-Exos and the abilities of EPC-Exos to protect against LPS were relayed by the horizontal shuttled miR-126. • Transferred miR-126 to target endothelial cells downregulated SPRED1 and implicated RAF/ERK signaling pathways in the reparative process in rat model of lung injury. Endothelial progenitor cell (EPC) has potential to attenuate pulmonary inflammation and injury. As a pivotal paracrine entity of stem cells, whether EPC-derived exosomes (EPC-Exos) contribute to acute lung injury (ALI) remains unknown. Exosomes were purified from conditional medium of EPCs, and then characterized by electron micrograph and immunoblotting. A model of ALI was induced by lipopolysaccharide (LPS) and then rats were transplanted with EPC-Exos. The underlying mechanisms of action of EPC-Exos were examined in vitro endothelial functional assays including the TEER, proliferation (CKK-8), angiogenesis and migration. A possible underlying mechanism was examined by western blotting and further animal studies. Administration of EPC-Exos ameliorated LPS-induced ALI and restored the in vivo pulmonary integrity. EPC-Exos enhanced the proliferation, migration and tube formation of the endothelial cells (ECs). Furthermore, we found that miR-126 was enriched in EPC-Exos and can be delivered onto ECs. Modification of EPCs through miR-126 knockdown can diminish their exosomes function in vitro, indicative of the abilities of EPC-Exos to protect against LPS were inherited by the horizontal shuttled miR-126. Luciferase reporter assays confirmed that miR-126 could target SPRED1. Additionally, the miR-126 transferred to target endothelial cells resulted in subsequent downregulation of SPRED1 and promoted RAF/ERK signaling pathways and subsequent improvement in endothelial cell function. Our study revealed a novel role of exosomal miRNAs in EPC-mediated therapy, suggesting that the clinical application of EPC-Exos might represent a strategy in ALI/ARDS.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Resveratrol promotes oxidative stress to drive DLC1 mediated cellular senescence in cancer cells

Highlights: • Resveratrol stimulates senescence-associated proteins to induce cellular senescence. • Resveratrol causes mitochondrial dysfunction to promote ROS production. • DLC1 is essential for resveratrol induced senescence by promoting ROS production. • DLC1 induces cellular senescence through FoxO3a/NF-κB signaling mediated by SIRT1. • ROS production as the cause of resveratrol to induce DNA damage in cancer cells. Induction of cellular senescence represents a novel strategy to inhibit aberrant proliferation of cancer cells. Resveratrol is gaining attention for its cancer preventive and suppressive properties. Tumor suppressor gene DLC1 is shown to induce apoptosis, suppress migration and invasion in various cancer cells. However, the function of DLC1 in cancer cellular senescence is unclear. This study was designed to investigate the biological role of DLC1 in resveratrol induced cancer cellular senescence. Our results showed that resveratrol inhibited proliferation of cancer cell lines (MCF-7, MDA-MB-231 and H1299) and induced senescence along with increase of SA-β-gal activity and regulation of senescence-associated molecular markers p38MAPK, p-p38MAPK, p27, p21, Rb and p-Rb protein. The underlying mechanism was that resveratrol induced mitochondrial dysfunction with reduction of mitochondrial membrane potential, down-regulation of MT-ND1, MT-ND6 and ATPase8 in transcript level and down-regulation of PGC-1α in protein level to result in ROS production. With ROS elevation, resveratrol decreased DNMT1 and increased DLC1 expression significantly. However, after ROS scavenger NAC was added to the cancer cells treated by resveratrol, DNMT1, DLC1 and senescence-associated molecular markers were reversed. This reveals that resveratrol induced cancer cellular senescence through DLC1 in a ROS-dependent manner. Silencing DLC1 markedly attenuated SA-β-gal activity and p38MAPK, p27 and p21 protein levels, and increased Rb expression, indicating that resveratrol promoted senescence via targeting DLC1. Moreover, DLC1 promoted senescence through FoxO3a/NF-κB signaling mediated by SIRT1 after resveratrol treatment. Finally, resveratrol increased ROS production to induce DNA damage with p-CHK1 up-regulation and result in cancer cellular senescence. This is the first time to investigate resveratrol induced cancer cellular senescence by primarily targeting DLC1. Induction of cellular senescence by resveratrol may represent a novel anticancer mechanism.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

TCEA1 regulates the proliferative potential of mouse myeloid cells

Highlights: • shRNA library screening identifies functional regulators for myelopoiesis. • TCEA1 is required for balance between proliferation and differentiation. • Inactivation of TCEA1 disrupts definitive myelopoiesis. • Dysregulation of TCEA1 leads to the abnormal expression of genes for myelopoiesis. Leukemia is a malignance with complex pathogenesis and poor prognosis. Discovery of noval regulators amenable to leukemia could be of value to gain insight into the pathogenesis, diagnosis and prognosis of leukemia. Here, we conducted a large-scale shRNA library screening for functional regulators in the development of myeloid cells in primary cells. We identified eighteen candidate regulators in the primary screening. Those genes cover a wide range of cellular functions, including gene expression regulation, intracellular signaling transduction, nucleotide excision repair, cell cycle control and transcription regulation. In both primary screening and validation, shRNAs targeting Tcea1, encoding the transcription elongation factor A (SII) 1, exhibited the greatest influence on the proliferative potential of cells. Knocking down the expression of Tcea1 in the 32Dcl3 myeloid cell line led to enhanced proliferation of myeloid cells and blockage of myeloid differentiation induced by G-CSF. In addition, silence of Tcea1 inhibited apoptosis of myeloid cells. Thus, Tcea1 was identified as a gene which can influence the proliferative potential, survival and differentiation of myeloid cells. These findings have implications for how transcriptional elongation influences myeloid cell development and leukemic transformation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Effects of the tumor suppressor PTEN on biological behaviors of activated pancreatic stellate cells in pancreatic fibrosis

Highlights: • The PTEN level decreased in DBTC-induced pancreatic fibrosis. • PTEN expression correlates with the activation and apoptosis of PSCs in vivo. • PTEN modulation of activated PSCs involves the AKT and FAK/ERK pathways. • WT PTEN affects anti-fibrotic activity by regulating PSC behaviors in vitro. Pancreatic stellate cells (PSCs), when activated, are characterized by proliferation and collagen synthesis, and contribute to extracellular matrix deposition in pancreatic fibrosis. Concomitantly, fibrosis is linked with the loss of PTEN (phosphatase and tensin homolog) protein in several organs. This study investigated the association between PTEN protein levels and the activated or apoptotic status of PSCs in a rat model of chronic pancreatitis. In addition, the activation status and biological behaviors of culture-activated PSCs were analyzed after lentiviral transfection with wildtype or mutant (G129E) PTEN for upregulation, or PTEN short hairpin RNA for downregulation, of PTEN. In vivo, PTEN levels gradually decreased during pancreatic fibrosis, which positively correlated with apoptosis of activated PSCs, but negatively with PSC activation. In vitro, activated PSCs with wildtype PTEN showed less proliferation, migration, and collagen synthesis compared with control PSCs, and greater numbers were apoptotic; activated PSCs with mutant PTEN showed similar, but weaker, effects. Furthermore, AKT and FAK/ERK signaling was involved in this process. In summary, activated PSCs during pancreatic fibrosis in vivo have lower levels of PTEN. In vitro, PTEN appears to prevent PSCs from further activation and promotes apoptosis through regulation of the AKT and FAK/ERK pathways.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

MicroRNA-98 promotes drug resistance and regulates mitochondrial dynamics by targeting LASS2 in bladder cancer cells

MicroRNA-98(miR-98) has been shown to be critical for tumorigenesis, however its involvement in bladder cancer are unclear. The present study aims to investigate the expression, biological roles and potential mechanisms of miR-98 in human bladder cancer. We found that miR-98 was upregulated in bladder urothelial carcinoma tissues compared with adjacent normal tissues. In addition, miR-98 expression was higher in bladder cancer cell lines than in uroepithelial cell line SV-HUC-1. Functional studies revealed that miR-98 mimic promoted proliferation of T24 cells while miR-98 inhibitor inhibited proliferation of BIU-87 cells. Moreover, miR-98 mimic increased cisplatin/doxorubicin resistance and inhibited apoptosis in T24 cells, while miR-98 inhibitor decreased chemoresistance and facilitated apoptosis in BIU-87 cells. Further experiments using MitoTracker and JC-1 staining showed that miR-98 could regulate mitochondrial fission/fusion balance and mitochondrial membrane potential. Western blot showed that miR-98 upregulated cyclin D1, p-Drp1 and Drp1. Using luciferase reporter assay, we demonstrated that LASS2 acted as a direct target of miR-98. LASS2 overexpression induced mitochondrial fusion and downregulated mitochondrial potential, with decreased p-Drp1 status. Additionally, LASS2 siRNA abrogated the effects of miR-98 mimic on Drp1phosphorylation and chemoresistance. We also found a negative correlation between LASS2 and miR-98 in bladder cancer tissues. In conclusion, our study demonstrates that miR-98 targets LASS2 and regulates bladder cancer chemoresistance through modulation of mitochondrial function.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

A dehydrated, aseptically-processed human amnion/chorion allograft accelerates healing in a delayed murine excisional wound model

Since chronic, non-healing wounds represent an increasing source of economic and temporal burden for patients who suffer from them and healthcare professionals that treat them, therapeutic modalities that promote closure of delayed and non-healing wounds are of utmost importance. Recent clinical results of allografts derived from amnion and chorion placental layers encourage further investigation of the mechanisms underlying clinical efficacy of these products for treatment of wounds. Here, we utilized a diabetic murine splinted excisional wound model to investigate the effects of a dehydrated human amnion/chorion-derived allograft (dHACA) on delayed wound healing, as well as the effects of dehydrated allograft derived solely from amnion tissue of the same donor. We examined wound healing by histological endpoint analysis, and we assessed other parameters relevant to functional wound healing in the wound bed including angiogenesis, macrophage phenotypes, proliferative activity, and gene expression. Herein we demonstrate that application of dHACA to a murine diabetic model of delayed wound progression results in better macroscale wound resolution outcomes, including rate of closure, compared to unaided wound progression, while dehydrated human amnion allograft (dHAA) fails to improve outcomes. Improved gross wound resolution observed with dHACA was accompanied by increased granulation tissue formation, proliferation and vascular ingrowth observed in the wound bed, early macrophage polarization towards anti-inflammatory phenotypes, and downregulation of pro-fibrotic gene expression. Overall, our data suggest that improvements in the rates of delayed wound closure observed from combined amnion/chorion allografts are associated with modulation of critical cellular and tissue processes commonly found to be dysregulated in delayed healing wounds, including proliferation, vascularization, inflammation, and re-epithelialization.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

MiR-205–5p suppresses angiogenesis in gastric cancer by downregulating the expression of VEGFA and FGF1

Highlights: • MiR-205-5p was commonly downregulated in GC tissues from TCGA database and our hospital, and these events were associated with a worse TNM stagedistant metastasis and poor survival. • MiR-205-5p and CD31 expressions were negatively inter-related within GC tissues from TCGA database and our hospital. • GC cell lines expressed lower level of miR-205-5p significantly as compared with the normal gastric cell line. • MiR-205-5p upregulation significantly impaired proliferation and colony formation of GC cells and neovascularization induced by GC cells in vitro and in vivo. • The angiogenesis and ERK-signaling were depressed by VEGFA and FGF1 downregulation induced by miR-205-5p overexpression. The miR-205-5p inhibitor promoted malignant phenotypes by enhancing VEGFA and FGF1 expressions, as well as the activation of ERK-signaling. Anti-angiogenic therapy represents one of the most promising treatment modalities for human cancers. However, the response to antiangiogenic therapy in gastric cancer (GC) remains dismal. To help identify new strategies for antiangiogenic therapy in GC, we evaluated miR-205–5p expression in GC tissues from TCGA database and our hospital, and its functions in angiogenesis were explored in vitro and in vivo. We investigated miR-205–5p expression and microvessel densities (MVDs) in GC tissues and liver metastases from patients. The function and mechanisms of miR-205–5p were examined in human cell lines and in xenograft mouse models. Associations between miR-205–5p expression and clinical characteristics were analyzed using either Pearson's χ{sup 2} test or Fisher's exact test. Differences in overall survival (OS) distributions were evaluated using the log-rank test. Differences in measurement data were compared using Student's t-test and one-way ANOVA. We found that miR-205–5p expression was downregulated in GC tissues and was negatively correlated with CD31 expression in both TCGA and our clinical samples. GC cell lines expressed low levels of miR-205–5p, and miR-205–5p upregulation significantly impaired the proliferation and angiogenesis of GC cells. Moreover, vascular endothelial growth factor A (VEGFA) and fibroblast growth factor 1 (FGF1) expression and activation of extracellular-related kinase (ERK) signaling were suppressed by miR-205–5p. MiR-205–5p inhibition promoted malignant phenotypes by enhancing VEGFA and FGF1 expression, as well as the activation of ERK signaling. Angiogenesis and ERK signaling were decreased in response to VEGFA and FGF1 downregulation induced by miR-205–5p overexpression. The dual-luciferase reporter assay showed that VEGFA and FGF1 were direct targets of miR-205–5p. Xenograft mouse models revealed that miR-205–5p suppressed tumor growth by inhibiting neovascularization. Altogether, these results demonstrate that miR-205–5p suppresses angiogenesis in GC by attenuating the expression of VEGFA and FGF1, indicating that upregulation of miR-205–5p may represent as an antiangiogenic therapy for GC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Nanostructured Electrolytes for Stable Lithium Electrodeposition in Secondary Batteries

Secondary batteries based on lithium are the most significant energy storage technology for contemporary portable devices. The lithium ion battery (LIB) in widespread commercial use today is a compromise technology. It compromises high energy, high power, and design flexibility for long cell operating lifetimes and safety. Materials science, transport phenomena, and electrochemistry in the electrodes and electrolyte that constitute such batteries are areas of active study worldwide because significant improvements in storage capacity and cell lifetime are required to meet new demands, including the electrification of transportation and for powering emerging autonomous aircraft and robotics technologies. By replacing the carbonaceous host material used as the anode in an LIB with metallic lithium, rechargeable lithium metal batteries (LMBs) with higher storage capacity and compatibility with low-cost, high-energy, unlithiated cathodes such as sulfur, manganese dioxide, carbon dioxide, and oxygen become possible. Large-scale, commercial deployment of LMBs are today limited by safety concerns associated with unstable electrodeposition and lithium dendrite formation during cell recharge. LMBs are also limited by low cell operating lifetimes due to parasitic chemical reactions between the electrode and electrolyte. These concerns are greater in rechargeable batteries that utilize other, more earth abundant metals such as sodium and to some extent even aluminum. Inspired by early theoretical works, various strategies have been proposed for alleviating dendrite proliferation in LMBs. A commonly held view among these early studies is that a high modulus, solid-state electrolyte that facilitates fast ion transport, is nonflammable, and presents a strong-enough physical barrier to dendrite growth is a requirement for any commercial LMB. Unfortunately, poor room-temperature ionic conductivity, challenging processing, and the high cost of ceramic electrolytes that meet the modulus and stability requirements have to date proven to be insurmountable obstacles to progress. In this Account, we first review recent advances in continuum theory for dendrite growth and proliferation during metal electrodeposition. We show that the range of options for designing electrolytes and separators that stabilize electrodeposition is now substantially broader than one might imagine from previous literature accounts. In particular, separators designed at the nanoscale to constrain ion transport on length scales below a theory-defined cutoff, and structured electrolytes in which a fraction of anions are permanently immobilized to nanoparticles, to a polymer network or ceramic membrane are considered particularly promising for their ability to stabilize electrodeposition of lithium metal without compromising ionic conductivity or room temperature battery operation. Furthermore, we review recent progress in designing surface passivation films for metallic lithium that facilitate fast deposition of lithium at the electrolyte/electrode interface and at the same time protect the lithium from parasitic side reactions with liquid electrolytes. An enticing finding from both theory and experiment is that simple film-forming halide salt additives in a conventional liquid electrolyte can substantially extend the lifetime and safety of LMBs.

25 ENERGY STORAGE↗