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DOE OSTI2021

Thermomechanical fatigue resistance of low temperature solder for multiwire interconnects in photovoltaic modules

Novel interconnect technologies leveraging low melting temperature solders, such as multiwire interconnects, are being deployed in photovoltaic (PV) modules for improved reliability through interconnect redundancy and lower thermal loads during interconnection and lamination. However, the equivalency of standardized accelerated testing to field conditions has not yet been established for these emerging technologies. In this study, the thermomechanical fatigue resistance of low temperature solder alloys is investigated and compared to that of conventional SnPb to assess the acceleration behavior of these alloys. While InSn is shown to have sufficient thermomechanical fatigue resistance on the order of that of SnPb, these results indicate Sn–Bi alloys may have poor thermomechanical fatigue resistance at field conditions. The results also show that Sn–Bi alloys have thermal cycling acceleration factors of less than one. This indicates that the standardized accelerated thermal cycling test, such as that in IEC 61215, will produce misleading results for Sn–Bi alloys and that unique testing is required for this PV module architecture. Though accelerated thermal cycling may be a meaningful qualification test for SnPb solder joints, these results suggest that mechanical loading may be a more appropriate test for Sn–Bi multiwire interconnects. This is due to the distinct processing and geometry of multiwire interconnects which may allow for mechanical, rather than strictly metallurgical interconnections.

14 SOLAR ENERGY↗

DOE OSTI2014

Miniband Transport in a Two-Dimensional Electron Gas with a Strong Periodic Unidirectional Potential Modulation

In this paper, we study the Bloch oscillations of a two-dimensional electron gas with a strong periodic potential-modulation and miniband transport along the field at low temperatures, assuming a free motion in the transverse direction. The dependence of the current on the field, the electron density, and the temperature is investigated by using a relaxation-time approximation for inelastic scattering. Moreover, for a fixed total scattering rate, the field dependence of the current is sensitive to the ratio of the elastic and inelastic scattering rates in contrast with the recent result of a multiband but otherwise similar model with a weak potential modulation.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗

DOE OSTI2013

Cadmium modulates adipocyte functions in metallothionein-null mice

Our previous study has demonstrated that exposure to cadmium (Cd), a toxic heavy metal, causes a reduction of adipocyte size and the modulation of adipokine expression. To further investigate the significance of the Cd action, we studied the effect of Cd on the white adipose tissue (WAT) of metallothionein null (MT{sup −/−}) mice, which cannot form atoxic Cd–MT complexes and are used for evaluating Cd as free ions, and wild type (MT{sup +/+}) mice. Cd administration more significantly reduced the adipocyte size of MT{sup −/−} mice than that of MT{sup +/+} mice. Cd exposure also induced macrophage recruitment to WAT with an increase in the expression level of Ccl2 (MCP-1) in the MT{sup −/−} mice. The in vitro exposure of Cd to adipocytes induce triglyceride release into culture medium, decrease in the expression levels of genes involved in fatty acid synthesis and lipid hydrolysis at 24 h, and at 48 h increase in phosphorylation of the lipid-droplet-associated protein perilipin, which facilitates the degradation of stored lipids in adipocytes. Therefore, the reduction in adipocyte size by Cd may arise from an imbalance between lipid synthesis and lipolysis. In addition, the expression levels of leptin, adiponectin and resistin decreased in adipocytes. Taken together, exposure to Cd may induce unusually small adipocytes and modulate the expression of adipokines differently from the case of physiologically small adipocytes, and may accelerate the risk of developing insulin resistance and type 2 diabetes. - Highlights: • Cd causes a marked reduction in adipocyte size in MT-null mice. • Cd enhances macrophage migration into adipose tissue and disrupt adipokine secretion. • MT gene alleviates Cd-induced adipocyte dysfunctions. • Cd enhances the degradation of stored lipids in adipocytes, mediated by perilipin. • Cd induces unusually small adipocytes and the abnormal expression of adipokines.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2013

Antitumor and chemosensitizing action of dichloroacetate implicates modulation of tumor microenvironment: A role of reorganized glucose metabolism, cell survival regulation and macrophage differentiation

Targeting of tumor metabolism is emerging as a novel therapeutic strategy against cancer. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been shown to exert a potent tumoricidal action against a variety of tumor cells. The main mode of its antineoplastic action implicates a shift of glycolysis to oxidative metabolism of glucose, leading to generation of cytotoxic reactive oxygen intermediates. However, the effect of DCA on tumor microenvironment, which in turn regulates tumor cell survival; remains speculative to a large extent. It is also unclear if DCA can exert any modulatory effect on the process of hematopoiesis, which is in a compromised state in tumor-bearing hosts undergoing chemotherapy. In view of these lacunas, the present study was undertaken to investigate the so far unexplored aspects with respect to the molecular mechanisms of DCA-dependent tumor growth retardation and chemosensitization. BALB/c mice were transplanted with Dalton's lymphoma (DL) cells, a T cell lymphoma of spontaneous origin, followed by administration of DCA with or without cisplatin. DCA-dependent tumor regression and chemosensitization to cisplatin was found to be associated with altered repertoire of key cell survival regulatory molecules, modulated glucose metabolism, accompanying reconstituted tumor microenvironment with respect to pH homeostasis, cytokine balance and alternatively activated TAM. Moreover, DCA administration also led to an alteration in the MDR phenotype of tumor cells and myelopoietic differentiation of macrophages. The findings of this study shed a new light with respect to some of the novel mechanisms underlying the antitumor action of DCA and thus may have immense clinical applications. - Highlights: • DCA modulates tumor progression and chemoresistance. • DCA alters molecules regulating cell survival, glucose metabolism and MDR. • DCA reconstitutes biophysical and cellular composition of tumor microenvironment. • DCA augments BMC cellularity, differentiation and repolarization of macrophages.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2014

Allosteric modulators of the hERG K{sup +} channel

Drugs that block the cardiac K{sup +} channel encoded by the human ether-à-go-go gene (hERG) have been associated with QT interval prolongation leading to proarrhythmia, and in some cases, sudden cardiac death. Because of special structural features of the hERG K{sup +} channel, it has become a promiscuous target that interacts with pharmaceuticals of widely varying chemical structures and a reason for concern in the pharmaceutical industry. The structural diversity suggests that multiple binding sites are available on the channel with possible allosteric interactions between them. In the present study, three reference compounds and nine compounds of a previously disclosed series were evaluated for their allosteric effects on the binding of [{sup 3}H]astemizole and [{sup 3}H]dofetilide to the hERG K{sup +} channel. LUF6200 was identified as an allosteric inhibitor in dissociation assays with both radioligands, yielding similar EC{sub 50} values in the low micromolar range. However, potassium ions increased the binding of the two radioligands in a concentration-dependent manner, and their EC{sub 50} values were not significantly different, indicating that potassium ions behaved as allosteric enhancers. Furthermore, addition of potassium ions resulted in a concentration-dependent leftward shift of the LUF6200 response curve, suggesting positive cooperativity and distinct allosteric sites for them. In conclusion, our investigations provide evidence for allosteric modulation of the hERG K{sup +} channel, which is discussed in the light of findings on other ion channels. - Highlights: • Allosteric modulators on the hERG K{sup +} channel were evaluated in binding assays. • LUF6200 was identified as a potent allosteric inhibitor. • Potassium ions were found to behave as allosteric enhancers. • Positive cooperativity and distinct allosteric sites for them were proposed.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2014

Effect of various antibiotics on modulation of intestinal microbiota and bile acid profile in mice

Antibiotic treatments have been used to modulate intestinal bacteria and investigate the role of intestinal bacteria on bile acid (BA) homeostasis. However, knowledge on which intestinal bacteria and bile acids are modified by antibiotics is limited. In the present study, mice were administered various antibiotics, 47 of the most abundant bacterial species in intestine, as well as individual BAs in plasma, liver, and intestine were quantified. Compared to the two antibiotic combinations (vancomycin + imipenem and cephalothin + neomycin), the three single antibiotics (metronidazole, ciprofloxacin and aztreonam) have less effect on intestinal bacterial profiles, and thus on host BA profiles and mRNA expression of genes that are important for BA homeostasis. The two antibiotic combinations decreased the ratio of Firmicutes to Bacteroidetes in intestine, as well as most secondary BAs in serum, liver and intestine. Additionally, the two antibiotic combinations significantly increased mRNA of the hepatic BA uptake transporters (Ntcp and Oatp1b2) and canalicular BA efflux transporters (Bsep and Mrp2), but decreased mRNA of the hepatic BA synthetic enzyme Cyp8b1, suggesting an elevated enterohepatic circulation of BAs. Interestingly, the two antibiotic combinations tended to have opposite effect on the mRNAs of most intestinal genes, which tended to be inhibited by vancomycin + imipenem but stimulated by cephalothin + neomycin. To conclude, the present study clearly shows that various antibiotics have distinct effects on modulating intestinal bacteria and host BA metabolism. - Highlights: • Various antibiotics have different effects on intestinal bacteria. • Antibiotics alter bile acid composition in mouse liver and intestine. • Antibiotics influence genes involved in bile acid homeostasis. • Clostridia appear to be important for secondary bile acid formation.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2014

Chronic infusion of lisinopril into hypothalamic paraventricular nucleus modulates cytokines and attenuates oxidative stress in rostral ventrolateral medulla in hypertension

The hypothalamic paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) play a critical role in the generation and maintenance of sympathetic nerve activity. The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. This study was designed to determine whether inhibition of the angiotensin-converting enzyme (ACE) in the PVN modulates cytokines and attenuates oxidative stress (ROS) in the RVLM, and decreases the blood pressure and sympathetic activity in renovascular hypertensive rats. Renovascular hypertension was induced in male Sprague–Dawley rats by the two-kidney one-clip (2K1C) method. Renovascular hypertensive rats received bilateral PVN infusion with ACE inhibitor lisinopril (LSP, 10 μg/h) or vehicle via osmotic minipump for 4 weeks. Mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and plasma proinflammatory cytokines (PICs) were significantly increased in renovascular hypertensive rats. The renovascular hypertensive rats also had higher levels of ACE in the PVN, and lower level of interleukin-10 (IL-10) in the RVLM. In addition, the levels of PICs, the chemokine MCP-1, the subunit of NAD(P)H oxidase (gp91{sup phox}) and ROS in the RVLM were increased in hypertensive rats. PVN treatment with LSP attenuated those changes occurring in renovascular hypertensive rats. Our findings suggest that the beneficial effects of ACE inhibition in the PVN in renovascular hypertension are partly due to modulation cytokines and attenuation oxidative stress in the RVLM. - Highlights: • Chronic ACE inhibition in PVN on renovascular hypertension was investigated. • 2K1C resulted in sympathoexcitation, increased plasma PICs and hypertension. • 2K1C rats had higher levels of cytokines and reactive oxygen species (ROS) in RVLM. • Chronic inhibiting PVN ACE attenuates cytokines and ROS in RVLM in hypertension.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

Protocatechuic aldehyde ameliorates experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway

An abnormal high mobility group box 1 (HMGB1) activation and a decrease in receptor for advanced glycation end-product (RAGE) play a key role in the pathogenesis of pulmonary fibrosis. Protocatechuic aldehyde (PA) is a naturally occurring compound, which is extracted from the degradation of phenolic acids. However, whether PA has anti-fibrotic functions is unknown. In this study, the effects of PA on the transforming growth factor-β1 (TGF-β1)-mediated epithelial–mesenchymal transition (EMT) in A549 cells, on the apoptosis of human type I alveolar epithelial cells (AT I), on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on bleomycin (BLM)-induced pulmonary fibrosis in vivo were investigated. PA treatment resulted in a reduction of EMT in A549 cells with a decrease in vimentin and HMGB, an increase of E-cadherin and RAGE, a reduction of HLF-1 proliferation with a decrease of fibroblast growth factor 2 (FGF-2) and platelet-derived growth factor (PDGF). Apoptosis of AT I was attenuated with an increase of RAGE. PA ameliorated BLM-induced pulmonary fibrosis in rats with a reduction of histopathological scores and collagen deposition, and a lower FGF-2, PDGF, α-smooth muscle actin (α-SMA) and HMGB1 expression, whereas higher RAGE was found in BLM-instilled lungs. Through the decrease of HGMB1 and the regulation of RAGE, PA reversed the EMT, inhibited HLF-1 proliferation as well as reduced apoptosis in AT I, and prevented pulmonary fibrosis in vivo. Collectively, our results demonstrate that PA prevents experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway. - Highlights: • PA prevents EMT, reduces the apoptosis of AT1 in vitro. • PA decreases proliferation of HLF-1, reduces PDGF and FGF expression in vitro. • PA prevents experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

Environmental exposure to lead induces oxidative stress and modulates the function of the antioxidant defense system and the immune system in the semen of males with normal semen profile

We investigated the associations between environmental exposure to lead and a repertoire of cytokines in seminal plasma of males with normal semen profile according to the WHO criteria. Based on the median lead concentration in seminal plasma, 65 samples were divided into two groups: low (LE) and high exposure to lead (HE). Differences in semen volume and the pH, count, motility and morphology of sperm cells were not observed between the examined groups. The total oxidant status value and the level of protein sulfhydryl groups as well as the activities of manganese superoxide dismutase and catalase were significantly higher in the HE group, whereas the total antioxidant capacity value and the activities of glutathione reductase and glutathione-S-transferase were depressed. IL-7, IL-10, IL-12, and TNF-α levels were significantly higher in the HE group compared with the LE group. Environmental exposure to lead is sufficient to induce oxidative stress in seminal plasma and to modulate antioxidant defense system. - Highlights: • Lead induces oxidative stress in seminal plasma in human. • Lead modulates antioxidant defense system in seminal plasma in human. • Lead does not change a Th1/Th2 imbalance in seminal plasma in human.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

Improved bioavailability of targeted Curcumin delivery efficiently regressed cardiac hypertrophy by modulating apoptotic load within cardiac microenvironment

Cardiomyocyte apoptosis acts as a prime modulator of cardiac hypertrophy leading to heart failure, a major cause of human mortality worldwide. Recent therapeutic interventions have focussed on translational applications of diverse pharmaceutical regimes among which, Curcumin (from Curcuma longa) is known to have an anti-hypertrophic potential but with limited pharmacological efficacies due to low aqueous solubility and poor bioavailability. In this study, Curcumin encapsulated by carboxymethyl chitosan (CMC) nanoparticle conjugated to a myocyte specific homing peptide was successfully delivered in bioactive form to pathological myocardium for effective regression of cardiac hypertrophy in a rat (Rattus norvegicus) model. Targeted nanotization showed higher cardiac bioavailability of Curcumin at a low dose of 5 mg/kg body weight compared to free Curcumin at 35 mg/kg body weight. Moreover, Curcumin/CMC-peptide treatment during hypertrophy significantly improved cardiac function by downregulating expression of hypertrophy marker genes (ANF, β-MHC), apoptotic mediators (Bax, Cytochrome-c) and activity of apoptotic markers (Caspase 3 and PARP); whereas free Curcumin in much higher dose showed minimal improvement during compromised cardiac function. Targeted Curcumin treatment significantly lowered p53 expression and activation in diseased myocardium via inhibited interaction of p53 with p300-HAT. Thus attenuated acetylation of p53 facilitated p53 ubiquitination and reduced the apoptotic load in hypertrophied cardiomyocytes; thereby limiting cardiomyocytes' need to enter the regeneration cycle during hypertrophy. This study elucidates for the first time an efficient targeted delivery regimen for Curcumin and also attributes towards probable mechanistic insight into its therapeutic potential as a cardio-protective agent for regression of cardiac hypertrophy. - Highlights: • Cardiomyocyte targeted Curcumin/CMC-peptide increases bioavailability of the drug. • Curcumin nanoparticle regresses cardiac hypertrophy by reducing myocyte apoptosis. • Targeted Curcumin shows higher efficacy over free Curcumin to regress hypertrophy. • Curcumin modulates p300-HAT axis to facilitate p53 degradation.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

Butyl paraben and propyl paraben modulate bisphenol A and estradiol concentrations in female and male mice

People are routinely exposed to the antimicrobial preservatives butyl paraben (BP) and propyl paraben (PP), as well as the monomer of polycarbonate plastics, bisphenol A (BPA). These chemicals are reliably detected in human urine and potentially interact. We investigated whether BP or PP exposure can modulate the concentrations of {sup 14}C-BPA and 17β-estradiol (E{sub 2}). Female and male CF1 mice were each given a subcutaneous injection of oil containing 0 (vehicle), 1, 3, or 9 mg BP or PP, then given a dietary supplement containing 50 μg/kg {sup 14}C-BPA. Radioactivity was measured in tissues through liquid scintillation counting. Significantly elevated {sup 14}C-BPA concentrations were observed following BP treatment in blood serum of both sexes, as well as the lungs, uterus, and ovaries of females and the testes and epididymides of males. Treatment with PP significantly elevated {sup 14}C-BPA concentrations in the uterus only. In another experiment, female and male CF1 mice were each injected with vehicle, 3 mg BP, or 3 mg PP, and E{sub 2} was measured in urine 2–12 h later. Whereas PP did not affect E{sub 2}, BP significantly elevated E{sub 2} 6–10 h after injection in females and 8 h after injection in males. These data indicate that BP and PP can alter the pharmacokinetics of BPA in vivo, and that BP can modulate E{sub 2} concentrations. These results are consistent with evidence that parabens inhibit enzymes that are critical for BPA and E{sub 2} metabolism, and demonstrate the importance of considering concurrent exposure to multiple chemicals when determining regulatory exposure limits. - Highlights: • We studied whether paraben exposure affects the distribution of oral {sup 14}C-BPA. • Elevated {sup 14}C–BPA was observed in mice given butyl or propyl paraben. • We also studied whether paraben exposure affects natural E{sub 2} levels in urine. • Elevated E{sub 2} was observed in mice given butyl, but not propyl, paraben. • Parabens may compete for enzymes that are critical for BPA and E{sub 2} metabolism.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

Pregnane and Xenobiotic Receptor gene expression in liver cells is modulated by Ets-1 in synchrony with transcription factors Pax5, LEF-1 and c-jun

Nuclear receptor PXR is predominantly expressed in liver and intestine. Expression of PXR is observed to be dysregulated in various metabolic disorders indicating its involvement in disease development. However, information available on mechanisms of PXR self-regulation is fragmentary. The present investigation identifies some of the regulatory elements responsible for its tight regulation and low cellular expression. Here, we report that the PXR-promoter is a target for some key transcription factors like PU.1/Ets-1, Pax5, LEF-1 and c-Jun. Interestingly, we observed that PXR-promoter responsiveness to Pax5, LEF-1 and c-Jun, is considerably enhanced by Ets transcription factors (PU.1 and Ets-1). Co-transfection of cells with Ets-1, LEF-1 and c-Jun increased PXR-promoter activity by 5-fold and also induced expression of endogenous human PXR. Site-directed mutagenesis and transfection studies revealed that two Ets binding sites and two of the three LEF binding sites in the PXR-promoter are functional and have a positive effect on PXR transcription. Results suggest that expression of Ets family members, in conjunction with Pax5, LEF-1 and c-Jun, lead to coordinated up-regulation of PXR gene transcription. Insights obtained on the regulation of PXR gene have relevance in offering important cues towards normal functioning as well as development of several metabolic disorders via PXR signaling. - Highlights: • The study identified cis-regulatory elements in the nuclear receptor PXR promoter. • Several trans-acting factors modulating the PXR-promoter have been identified. • PU.1/Ets-1, Pax5, LEF-1, c-Jun, LyF-VI and NF-1 act as modulators of the PXR-promoter. • Ets-1 in conjunction with LEF-1 and c-Jun exhibit 5-fold activation of the PXR-promoter. • Insights into PXR-regulation have relevance in normal and pathological conditions.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

Studying p53 family proteins in yeast: Induction of autophagic cell death and modulation by interactors and small molecules

In this work, the yeast Saccharomyces cerevisiae was used to individually study human p53, p63 (full length and truncated forms) and p73. Using this cell system, the effect of these proteins on cell proliferation and death, and the influence of MDM2 and MDMX on their activities were analyzed. When expressed in yeast, wild-type p53, TAp63, ΔNp63 and TAp73 induced growth inhibition associated with S-phase cell cycle arrest. This growth inhibition was accompanied by reactive oxygen species production and autophagic cell death. Furthermore, they stimulated rapamycin-induced autophagy. On the contrary, none of the tested p53 family members induced apoptosis either per se or after apoptotic stimuli. As previously reported for p53, also TAp63, ΔNp63 and TAp73 increased actin expression levels and its depolarization, suggesting that ACT1 is also a p63 and p73 putative yeast target gene. Additionally, MDM2 and MDMX inhibited the activity of all tested p53 family members in yeast, although the effect was weaker on TAp63. Moreover, Nutlin-3a and SJ-172550 were identified as potential inhibitors of the p73 interaction with MDM2 and MDMX, respectively. Altogether, the yeast-based assays herein developed can be envisaged as a simplified cell system to study the involvement of p53 family members in autophagy, the modulation of their activities by specific interactors (MDM2 and MDMX), and the potential of new small molecules to modulate these interactions. - Highlights: • p53, p63 and p73 are individually studied in the yeast S. cerevisiae. • p53 family members induce ROS production, cell cycle arrest and autophagy in yeast. • p53 family members increase actin depolarization and expression levels in yeast. • MDM2 and MDMX inhibit the activity of p53 family members in yeast. • Yeast can be a useful tool to study the biology and drugability of p53, p63 and p73.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

Quercetin reverses experimental pulmonary arterial hypertension by modulating the TrkA pathway

Pulmonary arterial hypertension (PAH) is characterized by excessive proliferation, resistance to apoptosis, and increased migration of pulmonary artery smooth muscle cells (PASMCs). We hypothesized that quercetin exerts protective effects against this disease; thus, a chronic hypoxia model of PAH was generated using male Sprague-Dawley rats, which were treated with quercetin. In this model, quercetin prevented the development of PAH, right ventricular hypertrophy, and vascular remodeling after exposure to hypoxia. Quercetin inhibited PASMC proliferation and increased the apoptosis of PASMCs in vivo. In vitro, quercetin significantly inhibited hypoxia-induced PASMC proliferation, arrested cells in G1/G0 and inhibited cell migration in a dose-dependent manner. Moreover, our results showed that quercetin increased cyclin D1 protein levels and decreased the protein expression of cyclin B1 and Cdc2. Additionally, quercetin altered the Bax/Bcl-2 ratio and reduced MMP2, MMP9, CXCR4, integrin β1, and integrin α5 expression. Using genome-wide microarray analysis, we found that factors regulating proliferation, apoptosis, cell cycle, and migration were related to the tyrosine receptor kinase A (TrkA) pathway. In addition, activation of the TrkA/AKT signaling cascade during hypoxia was inhibited by quercetin in a dose-dependent manner. Moreover, quercetin alone inhibited the TrkA/AKT signaling pathway, resulting in decreased PASMC migration, cell cycle arrest and the induction of apoptosis. Our data suggest that quercetin is a potential candidate for the treatment of hypoxia-induced PAH. - Graphical abstract: Graphical summary illustrating quercetin reversed hypoxia-induced PAH via modulating the TrkA signal cascade. - Highlights: • Quercetin ameliorate hypoxia-induced PAH and pulmonary arterial remodeling. • Quercetin reverses hypoxia-induced apoptosis resistance, cell cycle arrested and migration in PASMCs. • Quercetin alleviate experimental PAH partially by modulating the TrkA/AKT signaling pathway.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

Annexin A2-modulated proliferation of pulmonary arterial smooth muscle cells depends on caveolae and caveolin-1 in hepatopulmonary syndrome

We have established that annexin A2 (ANXA2) is an important factor in the experimental hepatopulmonary syndrome (HPS) serum-induced proliferation of pulmonary arterial smooth muscle cells (PASMCs). However, the detailed mechanism remains unclear. ANXA2 translocated to the caveolin-enriched microdomains (caveolae) in PASMCs upon HPS serum stimulation. The disruption of caveolae by Methyl-β-cyclodextrin (MβCD) alleviated the caveolae recruitment of ANXA2 and the ANXA2-mediated activation of ERK1/2 and NF-κB, so that ANXA2-modulated PASMC proliferation was suppressed. The over-expression of Cav-1 resulted in the relocation of ANXA2 from caveolae and negatively regulated ERK1/2 and NF-κB activation, which inhibited the ANXA2-modulated PASMC proliferative behavior. These data indicate that caveolae function as a signaling platform for ANXA2-induced proliferative behavior and Cav-1 participates upstream of ANXA2 in the activation of ERK1/2 and NF-κB.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

Neuromedin B and its receptor silencing suppresses osteoclast generation by modulating precursor proliferation via M-CSF/c-Fms/D-type cyclins

Neuromedin B (NMB), a mammalian bombesin-like peptide, regulates diverse physiological processes, such as energy metabolism, memory and fear behavior, and cellular growth, through its cognate receptor, NMBR. In this study, we report that NMB expression was upregulated during osteoclast development and that silencing NMB or NMBR attenuated osteoclast generation mediated by macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL). We found that knockdown of NMB or NMBR using a small hairpin RNA suppressed M-CSF-induced proliferation of osteoclast precursor cells without altering osteoclast differentiation. Interestingly, NMB or NMBR knockdown reduced the expression of the M-CSF receptor, c-Fms, which is an important modulator of osteoclast development. Consequently, NMB or NMBR silencing inhibited M-CSF/c-Fms-mediated downstream signaling pathways like activation of ERK and Akt and induction of D-type cyclins, cyclin D1 and D2. Moreover, knockdown of NMB or NMBR accelerated apoptosis in osteoclast lineage cells by inducing caspase-3, caspase-9, and Bim expression. In summary, our study demonstrates that the NMB/NMBR axis plays a pivotal role in osteoclast generation by modulating the proliferation and survival of osteoclast lineage cells. - Highlights: • NMB and NMBR expression is regulated during osteoclast development. • NMB/NMBR axis regulates osteoclast generation mediated by M-CSF and RANKL. • NMB/NMBR silencing suppresses M-CSF-induced osteoclast precursor proliferation. • NMB/NMBR silencing accelerates apoptosis in osteoclast lineage cells.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

CD4 + T cells promote renal cell carcinoma proliferation via modulating YBX1

Highlights: • RCC cells had better capacity than its surrounding normal kidney epithelial cells to recruit the CD4 + T cells. • Infiltrating CD4 + T cells promoted TGFβ1 expression in both RCC and T cells. • Infiltrating CD4 + T cells regulated RCC cells proliferation via modulating TGFβ1/YBX1/ HIF2α signals. • Targeting CD4 + T cell, TGFβ1, YBX1 and HIF2α may allow us to develop new and better therapies to suppress RCC progression and might be a potential target for the further research of RCC. Renal cell carcinoma (RCC) is a common urologic tumor and the third leading cause of death among urological tumors. Recent studies demonstrate that RCC tumors are more heavily infiltrated by lymphocytes than other cancers. However, the exact roles played by CD4 + T cells in RCC proliferation remain unknown. In this study, we cocultured RCC cells with CD4 + T cells. Stable knockdown of YBX1 in RCC cells was constructed. The effects of CD4 + T cells, TGFβ1 and YBX1 on RCC cells were investigated using cell viability assays. In situ RCC nude mouse model was used to observe the tumor growth. The potential mechanisms of CD4 + T cells and YBX1 in RCC cells proliferation were explored by qRT-PCR and western blot. Expression of CD4, Foxp3 and TGFβ1 in RCC were quantified by immunohistochemical staining. The results indicated that CD4, Foxp3 and TGFβ1 were significantly up-regulated in RCC tissues. Human clinical sample and in vitro cell lines studies showed that RCC cells had better capacity than its surrounding normal kidney epithelial cells to recruit the CD4 + T cells. In vivo mouse model studies were consistent with the results by in vitro cell lines studies showing infiltrating T cells enhanced RCC cell proliferation. qRT-PCR and western blot exhibited that CD4 + T cells could enhance RCC cell proliferation via activating YBX1/HIF2α signaling pathway. Furthermore, CD4 + T cells functioned through inducing TGFβ1 expression. In a word, infiltrating CD4 + T cells promoted TGFβ1 expression in both RCC and T cells and regulated RCC cells proliferation via modulating TGFβ1/YBX1/ HIF2α signals.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

A HIF1A/miR-485–5p/SRPK1 axis modulates the aggressiveness of glioma cells upon hypoxia

The high aggressiveness of gliomas remains a huge challenge to clinical therapies, and the hypoxic microenvironment in the core region is a critical contributor to glioma aggressiveness. In this study, it was found that miR-485–5p was low expressed within glioma tissue samples and cells. GO enrichment annotation indicated that the predicted downstream targets miR-485–5p were enriched in hypoxia response and decreased oxygen level. In glioma cells, miR-485–5p overexpression suppressed cell viability, migratory ability, and invasive ability under both normoxic and hypoxic conditions. Through direct binding, miR-485–5p suppressed SRPK1 expression. Under hypoxia, SRPK1 overexpression enhanced hypoxia-induced glioma cell aggressiveness and significantly reversed the effects of miR-485–5p overexpression. Moreover, HIF1A could target the miR-485–5p promoter region to inhibit the transcription. HIF1A, miR-485–5p, and SRPK1 form a regulatory axis, which modulates glioma cell aggressiveness under hypoxia. In conclusion, we identify a HIF1A/miR-485–5p/SRPK1 axis that modulates the aggressiveness of glioma cells under hypoxia. The axis could potentially provide new research avenues in the treatment of gliomas considering the hypoxic environment in its core.

60 APPLIED LIFE SCIENCES↗