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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 145 records · Page 8
All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

Salusin-β mediates high glucose-induced endothelial injury via disruption of AMPK signaling pathway

The dysregulated proliferation, migration, apoptosis and angiogenesis of endothelial cells are involved in diabetic endothelial dysfunction. The circulating salusin-β levels were increased in diabetic patients, and salusin-β contributes to diabetic cardiomyopathy in rats. However, the roles of salusin-β in diabetes mellitus-induced endothelial dysfunction are not fully understood. Herein, we demonstrated the increased expressions of salusin-β in human umbilical vein endothelial cells (HUVECs) cultured in HG medium. Exposure of HUVECs to HG inhibited the proliferation, migration, and angiogenesis, retarded cell cycle progression of endothelial cells, which were rescued by knockdown of salusin-β. We also established that silencing of salusin-β with adenoviruse-mediated shRNA reduced high glucose-induced apoptosis by up-regulating Bcl-2 expression and down-regulating Bax and caspase-3 expressions. Blockade of salusin-β ameliorated HG-induced suppression of adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Of note, pretreatment with AMPK inhibitor Compound C abolished salusin-β silencing-mediated endothelial protective effects. In summary, our results highlighted the involvement of salusin-β in HG-related endothelial dysfunction, and salusin-β contributed high glucose-induced endothelial injury via inactivation of AMPK signaling pathway. - Highlights: • Salusin-β contributed high glucose-induced endothelial injury via inactivation of AMPK signaling pathway. • Salusin-β are worthy for further exploration due to its potential therapeutics against neovascular diseases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Increase in proteins involved in mitochondrial fission, mitophagy, proteolysis and antioxidant response in type I endometrial cancer as an adaptive response to respiratory complex I deficiency

Pathogenic mtDNA mutations associated with alterations of respiratory complex I, mitochondrial proliferation (oncocytic-like phenotype) and increase in antioxidant response were previously reported in type I endometrial carcinoma (EC). To evaluate whether in the presence of pathogenic mtDNA mutations other mitochondrial adaptive processes are triggered by cancer cells, the expression level of proteins involved in mitochondrial dynamics, mitophagy, proteolysis and apoptosis were evaluated in type I ECs harboring pathogenic mtDNA mutations and complex I deficiency. An increase in the fission protein Drp1, in the mitophagy protein BNIP3, in the mitochondrial protease CLPP, in the antioxidant and anti-apoptotic protein ALR and in Bcl-2 as well as a decrease in the fusion protein Mfn2 were found in cancer compared to matched non malignant tissue. Moreover, the level of these proteins was measured in type I EC, in hyperplastic (the premalignant form) and in non malignant tissues to verify whether the altered expression of these proteins is a common feature of endometrial cancer and of hyperplastic tissue. This analysis confirmed in type I EC samples, but not in hyperplasia, an alteration of the expression level of these proteins. These results suggest that in this cancer mitochondrial fission, antioxidant and anti-apoptotic response may be activated, as well as the discharge of damaged mitochondrial proteins as adaptation processes to mitochondrial dysfunction.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Lycium barbarum polysaccharide protects against oxygen glucose deprivation/reoxygenation-induced apoptosis and autophagic cell death via the PI3K/Akt/mTOR signaling pathway in primary cultured hippocampal neurons

Lycium barbarum polysaccharide (LBP) is the main active ingredient of Lycium barbarum, which exhibits several beneficial effects, including neuroprotection, anti-aging and anti-oxidation. However, the mechanism by which LBP protects against cerebral ischemia/reperfusion-induced injury remains obscure. In this study, we found that LBP pretreatment greatly attenuated oxygen glucose deprivation/reperfusion (OGD/R) injury in primary cultured hippocampal neurons. LBP also suppressed OGD/R-induced lactate dehydrogenase (LDH) leakage, and ameliorated oxidative stress. In addition, LBP significantly reduced OGD/R-induced apoptosis and autophagic cell death. LBP caused the down-regulation of cleaved Caspase-3/Caspase-3, LC3II/LC3I and Beclin 1, as well as up-regulation of Bcl-2/Bax and p62. Furthermore, mechanistic studies indicated that LBP pretreatment increased p-Akt and p-mTOR levels after OGD/R. In summary, our results indicated that LBP protects against OGD/R-induced neuronal injury in primary hippocampal neurons by activating the PI3K/Akt/mTOR signaling pathway.

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

Traditional Chinese medication Tongxinluo attenuates apoptosis in ox-LDL-stimulated macrophages by enhancing Beclin-1-induced autophagy

Highlights: • TXL attenuates ox-LDL-impaired apoptosis in THP-1 macrophages. • TXL attenuates ox-LDL-impaired apoptosis in THP-1 macrophages by enhancing autophagy. • TXL treatment inhibits macrophage apoptosis by enhancing macrophage autophagy in advanced atherosclerotic plaques. • TXL stabilizes atherosclerotic plaques by attenuating macrophage apoptosis and enhancing Beclin-1-induced autophagy. In advanced atherosclerosis, a large number of necrotic core increases plaque vulnerability, which leads to the occurrence of acute atherothrombotic cardiovascular events. Macrophage apoptosis plays an important role in secondary necrosis. The present study aimed to examine and describe the effect of the traditional Chinese medication Tongxinluo (TXL) on macrophage apoptosis in advanced atherosclerotic plaques and to explore its mechanism. By observing the effect of TXL on ox-LDL-stimulated macrophage apoptosis, it was shown that TXL significantly inhibited ox-LDL-induced apoptosis of macrophages by enhancing autophagy. Therapeutic mechanism of TXL included increasing the expression of Beclin-1 and improving the dissociation of Bcl-2-Beclin-1 Complex. Apolipoprotein E knockout (apoE−/−) mice with a high fat diet were divided into four groups: saline group (Saline gavage), low dose TXL group (0.38 g/kg/d, gavage), medium dose TXL group (0.75 g/kg/day, gavage), and high dose TXL group (1.5 g/kg/day, gavage). 4 weeks after carotid-artery surgery, lentiviral of Beclin-1 silencing was injected through the tail vein. TXL treatment significantly reduced macrophage apoptosis dose-dependently and the result was blocked by Beclin-1 silencing. In addition, the increased Lc3b dots by TXL almost localized to macrophages in advanced atherosclerotic plaque. Compared with the same dose of TXL shBeclin-1 group, plaque area and vulnerability index of TXL groups decreased. The anti-apoptosis effects of TXL on atherosclerosis was related to the improvement of autophagy via Beclin-1.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

ShRNA-mediated knock-down of CXCL8 inhibits tumor growth in colorectal liver metastasis

Highlights: • Showed an up regulation of chemokines (1, 2, 3, 5 and 8) in the tumor invasion front compared to inner parts of the tumor in a xenograft model of colorectal liver metastasis. • Upregulation of CXCL8 in the invasion front of tumor cells is able to promote colorectal liver metastasis. • ShRNA mediated knockdown of CXCL8 in LS174T cells resulted in significantly decreased cell proliferation, migration and invasion in vitro and in a near complete reduction of tumor growth in vivo. • Results suggest an association between CXCL8 expression and progression of colorectal carcinoma and the development of colorectal liver metastases. • CXCL8 may serve as a potential therapeutic target for the treatment of colorectal liver metastasis. CXCL8 belongs to proinflammatory chemokines that are predominantly involved in neutrophil chemotaxis and degranulation. Several studies have suggested that secretion of CXCL8 from cancer cells have a profound effect on tumor microenvironment. In this study, in continuation to our previous work of understanding the global picture of invasion related genes in colorectal liver metastases, we clearly show an up-regulation of CXCL8 expression in the tumor cells at the invasion front as compared to the tumor cells in the inner parts of the tumor. Furthermore, ShRNA mediated down-regulation of CXCL8 resulted in inhibition of cell proliferation, viability and invasion in vitro and a near complete growth reduction of tumor in vivo. We showed that CXCL8 secreted by tumor cells at the invasion front were able to promote migration through angiogenesis by upregulating VEGFA and invasion via the AKT/GSK3β/β-catenin/MMP7 pathway by upregulating BCL-2 confirming the key role of CXCL8 during tumor progression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

TNIP1 alleviates hepatic ischemia/reperfusion injury via the TLR2-Myd88 pathway

Highlights: • Decreased TNIP1 was measured in hepatic I/R. • TNIP1 affected hepatocyte proliferation and apoptosis after H/R. • TNIP1 attenuated the inflammatory response in hepatocytes injured by H/R. • TNIP1 inhibited the TLR4-Myd88 signaling in hepatocytes injured by H/R. • TLR4 reversed improvement induced by TNIP1 in hepatocytes injured by H/R. Hepatic ischemia/reperfusion (I/R) injury induces oxidative stress, hepatocyte apoptosis, and release of inflammatory cytokines, which together causes liver damage and even organ dysfunction. TNF-α-induced protein 3-interacting protein 1 (TNIP1) reportedly decreases expression of genes associated with stress response and inflammation. Thus, we investigated the effects of TNIP1 on hepatic cells injury caused by hypoxia/reoxygenation (H/R). Reduced expression of TNIP1 was determined in I/R mice compared to normal mice. Then, TNIP1 transgene mice were used to determine the effects of TNIP1 on mice after treatment for I/R. In the normal transgene (NTG) group, serum liver damage markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and gamma glutamyl transferase (GGT) in I/R mice significantly increased compared to the sham-operated mice. However, in the TNIP1 transgene (TNIP1-TG) group, those levels in I/R mice were reduced than that in NTG mice. Additionally, cell viability and apoptosis in the hepatic cell line L02 were detected after H/R treatment, MTT assay showed that cell viability was inhibited after H/R treatment, but reversed after ad-TNIP1 transfection. Cell apoptosis also was inhibited after ad-TNIP1 transfection, as shown by the caspase-3 and caspase-9 levels and Bcl-2 and Bax values. Furthermore, TNIP1 overexpression also attenuated the inflammatory response of L02 cells after H/R treatment. Finally, treatment with TNIP1 reduced the elevated expression of TLR2, TLR4, and Myd88 after H/R injury, but overexpression of TLR4 reversed the effects of TNIP1. In conclusion, TNIP1 may protect H/R-induced hepatic cell injury by inhibiting the TLR4/Myd88 pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

CART peptide activates the Nrf2/HO-1 antioxidant pathway and protects hippocampal neurons in a rat model of Alzheimer's disease

Highlights: • CART peptide reduced the accumulation of Aβ in the hippocampus of AD rats. • CART peptide improved the cognitive function of AD rats. • CART peptide attenuated the oxidative stress damage in the hippocampus of AD rats. • CART activated the Nrf2/HO-1 pathway to exert antioxidation. • CART inhibit the apoptosis of hippocampal neurons. The accumulation of amyloid-beta (Aβ) and oxidative stress damage in the brain are recognized as early features of Alzheimer's disease (AD). The cocaine- and amphetamine-regulated transcript (CART) peptide may possibly play an antioxidative role in neurons. The aim of this study was to investigate the potential antioxidant mechanism of CART peptide in a rat model of AD. We microinjected of Aβ{sub 1-42} (2μl/4μg/hemisphere) into rat hippocampus to set a rat model of AD. A pre-microinjection of CART peptide (1μl/0.02μg/hemisphere) into rat hippocampus was administered for five consecutive days before Aβ{sub 1-42} treatment. We found that Aβ{sub 1-42} microinjection led to reduction of endogenous CART level in rat hippocampus. CART pretreatment improved the spatial memory and locomotor ability of AD rats. CART peptide decreased the Aβ{sub 1-42} and Aβ production-associated enzyme BACE1 levels. Moreover, CART peptide attenuated the oxidative stress damage with a concrete manifestation of increased MDA as well as decreased T-SOD, GSH and ATP levels in the hippocampus of Aβ{sub 1-42}-treated rat, which may be causatively implicated the activating of Nrf2/HO-1 signaling pathway. Furthermore, CART peptide attenuated neuronal apoptosis with decreased Bax, caspase-9 and caspase-3 levels and increased Bcl-2 level in rat hippocampus. Our results therefore indicate that CART peptide could serve as an antioxidant in early therapy for AD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Influence and mechanism of Angiotensin 1-7 on biological properties of normal prostate epithelial cells

Highlights: • Ang1-7 inhibit proliferation and EMT of prostate epithelial cells by inactivation of PI3K axis. • Ang1-7 can counteract oxidant stress in prostate by inhibition of VEGF and upregulation of NOS3. • Ang1-7 increase the mRNA level of antiapoptotic genes: BIRC5 and BCL-2 in PNT1A cells. • Ang1-7 can upregulate not only AT1-7/MAS expression but also classic angiotensin receptors. • Ang1-7 can upregulate the AR and ESR2 receptor but dowregulate ESR1 in PNT1A. The ACE2/Ang1-7/MAS axis was involved in the cell proliferation, migration and apoptosis of many types of reproductive tissues. The research was conducted on prostate epithelial cells, immortalized by Simian Virus 40. We examined the influence of Ang 1–7 on biological properties of PNT1A cells after 24- or 48-h treatment. The employed selective antagonists of angiotensin receptors allowed evaluation of the receptor mediating Ang1-7 action. Our data clearly indicate that Ang1-7 can decrease cell proliferation and epithelial-to-mesenchymal transition of PNT1A cells via inactivation of PI3K axis and modulation of expression of the NF-kB gene family. Furthermore, it counteracts oxidant stress and inflammation in prostate cells by inhibition of VEGF expression and MMPs activation as well as by modulating the level of ERα and ERβ. On the other hand, this heptapeptide can promote cell survival by alteration of expression of anti- and pro-apoptotic members as well as compensatory up-regulation of AR expression. Summary, the results confirm the existence of a complicated dependence networks between the various elements of the local RAS and steroid hormone receptor pathways in prostate gland. Furthermore, shows the chances of using ACE2/Ang1-7/MAS pathway as a novel therapeutic target in prevention and treatment of prostate diseases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Combination therapy with BH3 mimetic and hyperthermia tends to be more effective on anti-melanoma treatment

Highlights: • The anti-melanoma ability of ch282-5 is synergistically amplified by hyperthermia. • Combination therapy with ch282-5 and hyperthermia activates pro-apoptotic signaling and inhibits pro-survival signaling. • Ch282-5 combining with microwave hyperthermia remits pulmonary colonization of melanoma cells. Malignant melanoma has shown increased incidence and high mortality rate in the last three decades. In this study, we investigated whether combination therapy with ch282-5 (a novel BH3 mimetic) and microwave hyperthermia could display synergistic antitumor effects against melanoma. Our results indicated that combination therapy reduced the viability and proliferation of melanoma cells. Through inhibiting the expression of anti-apoptotic proteins of Bcl-2 and IAP family and activating MAPK proteins, combined hyperthermia enhanced ch282-5-induced apoptosis. Combination therapy also synergistically disturbed the mTOR/p70S6k signaling pathway, which is important for cell survival and migration. Moreover, our results showed that combination therapy remarkably suppressed melanoma cell migration in vitro and significantly reduced experimental pulmonary metastasis in vivo. In conclusion, our results indicate that combination therapy with ch282-5 and hyperthermia has synergistic antitumor effects and provides a possible therapeutic strategy for advanced melanoma.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

TKTL1 modulates the response of paclitaxel-resistant human ovarian cancer cells to paclitaxel

Highlights: • TKTL1 expression is associated with ovarian cancer cell chemoresistance. • The chemo-resistant mechanism of TKTL1 played in cells was investigated. • Metabolomics was used to find the role of TKTL1 in PPP pathway. • The function of TKTL1 was investigated in vivo. Transketolase-like 1 (TKTL1) plays an important role in the pentose phosphate pathway (PPP) branch. The main obstacle of ovarian cancer treatment is chemotherapeutic resistance. We investigated whether inhibiting TKTL1 in OC3/TAX300 cells could re-sensitize paclitaxel-resistant cells to paclitaxel and proposed a mechanism of action. Western blotting revealed that TKTL1 expression levels in OC3/Tax300 cells were significantly higher than those in OC3 cells. Inhibition of TKTL1 significantly decreased the cellular proliferation rate and IC50 for paclitaxel. Metabolomics revealed that NADPH levels were reduced in the si-TKTL1 group, whereas NADP{sup +} was increased compared with the level in the negative si-TKTL1 group. A 2.2-fold increase in the ROS level and an obvious increase in the cell apoptosis rate were observed in the si-TKTL1+paclitaxel group compared with those in the negative si-TKTL1+paclitaxel and OC3/Tax300 + paclitaxel groups. Western blotting revealed that Bax and Caspase 3 proteins were up-regulated, whereas Bcl-2 expression was down-regulated. Quantitative RT-PCR revealed no changes in gst-π or mrp1 gene expression in the three groups, whereas GSH levels were reduced in the si-TKTL1 group as verified by metabolomics. TKTL1 inhibition also reduced tumor growth in vivo. Collectively, TKTL1 down-regulation sensitized paclitaxel-resistant OC3/Tax300 ovarian cancer cells to paclitaxel.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

ZKSCAN3 promotes breast cancer cell proliferation, migration and invasion

Highlights: • ZKSCAN3 is upregulated in breast cancer tissue and cell lines. • Knocking down ZKSCAN3 suppresses breast cancer cell proliferation, enhances cell apoptosis and blocks cell cycle. • Knocking down ZKSCAN3 significantly inhibits breast cancer cell migration and invasion. • Knocking down ZKSCAN3 significantly inhibits breast tumor growth in vivo. • Knocking down ZKSCAN3 reduces activity of the Akt/mTOR pathway. ZKSCAN3, a zinc-finger transcription factor, which has been shown to be upregulated in several human cancer. However, the expression level, function and mechanism of ZKSCAN3 in breast cancer remains unknown. In the current study, immunohistochemistry, western blot and quantitative real time polymerase chain reaction (qRT-PCR) results showed that ZKSCAN3 was overexpressed in breast cancer tissue compared with normal breast tissue. Through analyzing the clinicopathological characteristics, we demonstrated that positive ZKSCAN3 expression predicted poor prognosis of patients with breast cancer. The expression level of ZKSCAN3 protein/mRNA in breast cancer cells (MCF-7 and MDA-MB-231) was higher than its expression in normal breast cells (HBL-100). Knocking down ZKSCAN3 via its short hairpin RNA (shRNA) in MCF-7 and MDA-MB-231 inhibited cell viability, migration and invasion. Western blot analysis showed that ZKSCAN3 silencing lead to significant decreases in the expression of Cyclin D1, B-cell lymphoma-2 (Bcl-2), and matrix metalloproteinase (MMP)-2/MMP-9, as well as increases in the expression of Bcl2 Associated X Protein (Bax) in breast cancer cells. Additionally, ZKSCAN3-shRNA expression markedly suppressed tumor growth in breast cancer xenograft mice. Finally, we demonstrated that silencing of ZKSCAN3 was able to inhibit Akt/mTOR signaling pathway by blocking p-Akt and p-mTOR protein expression in breast cancer cells. These results demonstrate that ZKSCAN3 plays a significant role in the progression of breast cancer. Therefore, ZKSCAN3 is a potential therapeutic target for breast cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Ubiquinol promotes retinal ganglion cell survival and blocks the apoptotic pathway in ischemic retinal degeneration

Highlights: • Ubiquinol treatment promotes RGC survival in the ischemic retina. • Ubiquinol treatment blocks astroglial and microglial activation in the ischemic retina. • Ubiquinol treatment prevents apoptotic cell death by modulating the Bax/Bad/Bcl-xL pathway in the ischemic retina. Coenzyme Q10 (CoQ{sub 10}) protects retinal ganglion cells (RGCs) in experimental retinal ischemia and glaucoma by scavenging reactive oxygen species. We tested whether a diet supplemented with ubiquinol, the reduced form of CoQ{sub 10}, promotes RGC survival and blocks the apoptotic pathway in ischemic mouse retina induced by acute high intraocular pressure (IOP) elevation. Ubiquinol (1%) treatment significantly promoted RGC survival at 2 weeks after ischemia/reperfusion. The ubiquinol treatment significantly blocked activation of astroglial and microglial cells in the ischemic retina at 2 weeks. While the ubiquinol treatment significantly decreased active Bax protein expression in the ischemic retina, phosphorylation of Bad at serine 112 and Bcl-xL protein expression were preserved in the ubiquinol-treated ischemic retina at 12 h. Consistently, the ubiquinol treatment prevented apoptotic cell death by blocking caspase-3 cleavage. These results suggest that the ubiquinol enhances RGC survival by modulating the Bax/Bad/Bcl-xL-mediated apoptotic pathway in the ischemic retina. Ubiquinol has therapeutic potential for ameliorating elevated IOP-induced ischemic retinal degeneration.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Selenoprotein S protects against adipocyte death through mediation of the IRE1α-sXBP1 pathway

As the most conserved branch of the unfolded protein response (UPR), the inositol-requiring enzyme 1a (IRE1a)/X-box binding protein 1 (XBP1) pathway plays crucial roles in cell survival and cell death by upregulating UPR-associated genes involved in protein entry into the endoplasmic reticulum (ER) and ER-associated degradation (ERAD). Selenoprotein S (SelS) is localized to the ER membrane and involved in ERAD. Although SelS plays an important role in restoring ER stress, the SelS-dependent protective mechanisms against cell death remain unclear. Here, using an inducible SelS knockdown (KD) 3T3-L1 cell model, we showed that SelS KD resulted adipocyte death, which was associated with imbalance of the Bcl-2 family members. Furthermore, SelS KD decreased spliced XBP1 (sXBP1), increased IRE1α and p-JNK, suggesting a role of SelS in the modulation of the IRE1α-sXBP1 pathway. Moreover, adipocyte death induced by SelS suppression can be inhibited by overexpression of sXBP1. Thus, it is proposed that SelS promotes cell survival through the IRE1α-XBP1 signaling pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Platycodin D inhibits oxidative stress and apoptosis in H9c2 cardiomyocytes following hypoxia/reoxygenation injury

Highlights: • PD improves the cell viability in H/R-stimulated H9c2 cells. • PD represses oxidative stress in H9c2 cells exposed to H/R treatment. • PD suppresses apoptosis in H9c2 cells exposed to H/R treatment. • PD induces the activation of Akt/Nrf2/HO-1 pathway in H/R-stimulated H9c2 cells. Myocardial ischemia/reperfusion (I/R) injury is a complex pathophysiological process related to the occurrence of myocardial infarction (MI). Oxidative stress is known to play a crucial role in the pathogenesis of I/R injury. Platycodin D (PD) is an active natural saponin that possesses strong anti-oxidant activity. The aim of the present study was to investigate the effect of PD on myocardial I/R injury. An in vitro hypoxia/reoxygenation (H/R) model was established in cardiomyocyte H9c2 cells. The results showed that PD improved the cell viability in H/R-stimulated H9c2 cells. The H/R-induced increase in the production of reactive oxygen species (ROS) and malondialdehyde (MDA), and decrease in the activities of superoxide dismutase (SOD) and catalase (CAT) were reversed by PD pretreatment. The histone-associated DNA fragment was increased by H/R stimulation, while decreased after PD treatment. Besides, PD pretreatment reduced the expressions of Bax and cleaved caspase-3, while induced Bcl-2 expression in H/R-induced H9c2 cells. Furthermore, PD was found to induce the activation of Akt/Nrf2/HO-1 pathway. The inhibitor of Akt, LY294002, attenuated the effects of PD on H/R-induced H9c2 cells. These findings indicated that PD exerted its protective effect via inducing the activation of Akt/Nrf2/HO-1 pathway. Our work provided new insights into the potential therapeutic role of PD in myocardial I/R injury.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Deletion of ApoM gene induces apoptosis in mouse kidney via mitochondrial and endoplasmic reticulum stress pathways

Highlights: • Deletion of ApoM gene caused abnormal changes in mitochondria in mouse kidney. • Deletion of ApoM gene caused endoplasmic reticulum stress in mouse kidney. • Effect of ApoM gene deletion on apoptosis was determined in vivo and in vitro. • Deletion of ApoM gene caused upregulation of renal apoptosis in mouse. Apolipoprotein M (ApoM) is involved in lipid metabolism, and especially is involved in reverse cholesterol transport. However, the relationship between ApoM and apoptosis has been rarely reported. This study aimed to investigate the effect of ApoM on apoptosis using an ApoM gene-deficient mice (ApoM{sup −/−}) model and a mouse mesangial cell model with suppressed ApoM gene expression. First, we observed by transmission electron microscopy that mitochondrial damage and endoplasmic reticulum stress were abnormally altered in the kidneys of ApoM{sup −/−} mice compared with wild-type mice, showing mitochondrial swelling, vacuolization, myeloid changes, and expansion of the rough endoplasmic reticulum. At the molecular level, the expression of pro-apoptotic related proteins such as AIF, Bax, chop, clever-caspase 3, clever-caspase 7, clever-caspase 9, and clever-caspase 12 increased, and the expression of anti-apoptotic protein Bcl-2 decreased. Secondly, by interfering with the expression of the ApoM gene in mouse mesangial cells, we found that, compared with the control group (NC-si), the cells of the experimental group (siApoM) showed decreased cell viability, nuclear chromatin condensation, nuclear lysis, and an increased proportion of early apoptotic cells. The results in cells at the molecular level were consistent with those at the tissue level. These data indicated that the deletion of the ApoM gene led to upregulation of apoptosis in mouse kidney tissues and mesangial cells through the mitochondrial and endoplasmic reticulum pathways.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

A novel role for Bcl2l13 in promoting beige adipocyte biogenesis

Highlights: • Bcl2l13 expression is induced in Browning of white adipose tissues in Mice. • Knockdown of Bcl2l13 in beige adipocytes represses adipogenesis and thermogenic programing. • Bcl2l13 induces thermogenic programing by regulating mitochondrial dynamic and biogenesis. Bcl2l13 is a member of the Bcl-2 family that has been found to play a central role in regulating apoptosis. Recently Bcl2l13 has been reported to induce mitophagy as a functional mammalian homolog of Atg32. However, the role of Bcl2l13 in adipose tissue has not been investigated yet. In the present study, we found that Bcl2l13 expression was increased in white adipose tissue browning process stimulated by cold exposure or β3-adrenergic agonist CL-316,243 in vivo as well as during brown adipocytes differentiation in vitro. Moreover, Bcl2l13 disruption dramatically inhibited the browning program of preadipocytes, evidenced by reduced Prdm16, Ucp1, Dio2 and Adrb3 expression. Our findings revealed that the inhibition effect of Bcl2l13 disruption on browning program may be independent of altering autophagy activity, but through regulating mitochondrial dynamic and biogenesis, supported by decreased mitochondrial fission/fussion genes, PGC-1α and mitochondrial respiratory chain complexes expression. Taken together, our study uncovered a novel function of Bcl2l13 in adipocytes differentiation and promoting browning program.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Nuclear import of transcriptional corepressor BCOR occurs through interaction with karyopherin α expressed in human periodontal ligament

Highlights: • Human periodontal ligament cells express karyopherin α (KPNA) of three subclasses. • BCL6 corepressor (BCOR) is translocated to the nucleus by KPNA2, 4, and 6. • BCOR interacts with KPNA through nuclear localization signal 1. • BCOR mutation causing OFCD syndrome downregulates the SMAD4-SHH-NFIC pathways. Mutations in the gene encoding BCL-6 corepressor (BCOR) are responsible for oculofaciocardiodental (OFCD) syndrome, which is a rare X-linked dominant disorder characterized by radiculomegaly of permanent teeth as the most typical symptom. To function as a transcriptional corepressor, BCOR needs to enter the nucleus; however, the molecular pathway for its nuclear translocation during dental root formation remains unclear. The purpose of this study was to determine the mechanism underlying BCOR transport into the nucleus. Our results showed that human periodontal ligament (PDL) cells expressed karyopherin α (KPNA)2, KPNA4, and KPNA6 belonging to a family of nuclear import proteins, which interacted with BCOR in the immunoprecipitation assay. Site-directed mutagenesis targeting the two nuclear localization signals (NLSs) within BCOR reduced its nuclear translocation; however, co-expression of KPNA2, KPNA4, or KPNA6 with BCOR carrying a previously described mutation which eliminated one of the two NLSs significantly increased nuclear accumulation of the mutant BCOR, indicating participation of KPNA in BCOR nuclear translocation. Comparative expression profiling of PDL cells isolated from normal and OFCD patients revealed significant downregulation of SMAD4, GLI1, and nuclear factor 1-C (NFIC) mRNA expression, suggesting that BCOR mutations cause hyperactive root formation in OFCD syndrome by inhibiting SMAD4-Hedgehog-NFIC signaling implicated in dental root development. Our study contributes to understanding of the mechanisms providing nuclear import of BCOR during root formation.

60 APPLIED LIFE SCIENCES↗