Competition between Initial CO2 Electroreduction and Hydrogen Evolution Reaction on Cu Catalysts in Acidic Media: Role of Specifically Adsorbed Halide Anions.

The role of halide anions and competing mechanisms between initial CO2 electroreduction pathways and hydrogen evolution reaction (HER) are systematically identified at halide anions modified Cu(111)/H2O interfaces based on density functional theory calculations in this paper. The present results show that halide anions modified Cu(111)/H2O interfaces can notably enhance electroreduction activity of CO2 into CO. Simultaneously, it is concluded that the specifically adsorbed halide anions modified Cu electrodes can inhibit HER by studying competing HER mechanisms, and thus the enhanced CO2 electroreduction activity can be ascribed to the suppressed HER. The origin of enhanced CO production activity and inhibited HER is further scrutinized. The present results show that the presence of halide anions can lead to stronger CO adsorption and the increased adsorption strength of CO can explain easier CO production based on the Sabatier principle. Interestingly, the calculated results show that the presence of halide anions does not exert an effect on H adsorption strength, which is regarded as a key descriptor of HER activity, implying that halide anions modified Cu electrodes may be not able to directly lead to the inhibited HER. However, the present results indicate that co-adsorbed CO can weaken adsorption strength between H and Cu electrodes and thus result in inhibited HER and decreased HER activity. The upshift of d-band centers of surface Cu atoms due to modification of halide anions may be a reason for stronger CO adsorption, whereas the downshift of the d-band center due to the presence of co-adsorbed CO can lead to a weakening effect on H adsorption strength. Our present insights into the role of halide anions can aid in designing an optimal electrolyte and developing electrocatalysts that are more selective toward CO2 electroreduction than HER.

Theoretical understanding of the effect of specifically adsorbed halide anions on Cu-catalyzed CO2 electroreduction activity and product selectivity.

Initial CO2 electroreduction into CO and its subsequent electroreduction pathways were selected to study the effect of specifically adsorbed halide anions X- (X = F, Cl, Br, I) on CO2 electroreduction activity and product selectivity at Cu(111)/H2O interfaces via DFT calculations. The calculated results show that the presence of halide anions can exert a notable effect on the CO2 adsorption characteristics and that chemically adsorbed CO2 molecules can be formed. Furthermore, the halide-anion-modified Cu(111)/H2O interfaces could significantly enhance the initial CO2 electroreduction into CO activity, which is regarded as the rate-determining step during CO2 electroreduction at clean Cu(111)/H2O interfaces. Analysis of the initial CO2 electroreduction and Volmer reaction pathways showed that the halide-anion-modified Cu(111)/H2O interfaces could suppress the HER and thus improve the CO2 electroreduction activity and product selectivity. It is speculated that the enhanced initial CO2 electroreduction activity at the F--, Cl--, Br--, and I--modified Cu(111)/H2O interfaces may originate from the decreased work functions and anion radical ·CO2- formations. Simultaneously, we concluded that dimer OCCO formations in the presence of halide anions were more favorable than CHO during CO electroreduction according to the order of I- > Br- > Cl- > F- and could result in the production of C2 product, suggesting an improved CO2 electroreduction product selectivity. The present analyses of electronic structure may explain the more favorable OCCO formations in the order of I- > Br- > Cl- > F-. The present understanding of this effect will provide an improved scientific guideline for the control of CO2 electroreduction pathways and design of more efficient electrocatalysts.

PEPCK Coordinates the Regulation of Central Carbon Metabolism to Promote Cancer Cell Growth.

Phosphoenolpyruvate carboxykinase (PEPCK) is well known for its role in gluconeogenesis. However, PEPCK is also a key regulator of TCA cycle flux. The TCA cycle integrates glucose, amino acid, and lipid metabolism depending on cellular needs. In addition, biosynthetic pathways crucial to tumor growth require the TCA cycle for the processing of glucose and glutamine derived carbons. We show here an unexpected role for PEPCK in promoting cancer cell proliferation in vitro and in vivo by increasing glucose and glutamine utilization toward anabolic metabolism. Unexpectedly, PEPCK also increased the synthesis of ribose from non-carbohydrate sources, such as glutamine, a phenomenon not previously described. Finally, we show that the effects of PEPCK on glucose metabolism and cell proliferation are in part mediated via activation of mTORC1. Taken together, these data demonstrate a role for PEPCK that links metabolic flux and anabolic pathways to cancer cell proliferation.

Theoretical evaluation of the effect of bimetallic Au-based alloy catalysts on initial N2 electroreduction pathways.

Theoretical studies on the effect of bimetallic Au-based alloy catalysts on initial N2 electroreduction pathways at the present simulated electrode/aqueous interfaces based on DFT calculations are conducted in this work. The calculated results indicate that the alloying of Au with the transition metals Ni, Pd, Pt, Ru and Ta can facilitate the activation of N2 molecules in the presence of the electrode/aqueous interface, which may be derived from the kinetic overpotential of the outer Helmholtz plane. The N2 reduction pathway may be adsorption strength-dependent on N2, in which the incorporation of transition metals with a strong chemical affinity for N2 molecules may lead to a dissociative mechanism via the initial NN bond cleavage pathway, whereas the incorporation of transition metals with medium N2 binding strength may make N2 reduction proceed by the associative mechanism via the initial N2H formation pathway. The barriers of the initial N2 electroreduction into N2H species can be notably decreased after alloying Au with Ni, Pd, Pt, Ru and Ta compared with that on the Au electrode and the lowest N2H formation barriers can be obtained in these bimetallic Au-based alloy surfaces with an atomic ratio of 1 : 1, suggesting the strongest electrocatalytic activity. Further changing the atomic ratio leads to a notably increased formation barrier of N2H species, which can be explained by the Sabatier principle. It is concluded that the incorporation of Ni, Pd, Pt and Ru into Au can remarkably enhance the electrocatalytic activity since the HER barriers are notably higher than those of N2H formation, whereas the alloying of Au with Ta may not be able to effectively improve the N2 reduction performance due to the uninhibited HER. The present theoretical evaluations provide a promising method to design efficient bimetallic alloy electrocatalysts for N2 electroreduction into NH3 products.

Mechanistic insights into potential dependence of CO electrochemical reduction into C1 products based on a H coverage-dependent Cu(111)/H2O interface model.

A H coverage-dependent Cu(111)/H2O interface model incorporated with electronic structure analysis is employed to investigate the potential dependence of CO electroreduction into C1 products with the aim of solving the long dispute over CO2 electrocatalytic reduction mechanisms. The results indicate that CH4 formation mainly proceeds through CO, CHO, CH2O, CH2OH and CHx (x = 2 and 3) species at various applied potentials. CH3OH may be formed via a CH3O intermediate at high overpotential and the present study can confirm that CH3OH is only produced in a trace amount as detected in experiments. The high overpotential results in the formation of CH4, explaining the experimentally required high overpotential on Cu. The calculated energetics concludes that CO electroreduction into CHO may be a potential-limiting step, being regarded as the origin of the required high overpotentials for CO2 electroreduction in this paper. The electronic structure calculations show that more electronic transfer to the adsorbed H atoms occurs with increasing H coverage, which can be considered as the origin of the more negative electrode potentials. Interestingly, it is observed that the s orbital of the C atom in the valence shell of the adsorbed CO molecule gains more and more electrons, whereas the s orbital of the O atom gains less and less electrons, and even loses electrons with increasing H coverage, implying easier and easier proton transfer towards the C-center site. Thus, the easier occurrence of CO electroreduction may be ascribed to the more electron transfer into the s orbital of the C atom at high overpotential. We believe that the present study represents theoretical progress to systematically study potential-dependent CO2 electroreduction mechanisms on Cu electrodes.

Theoretical insights into the effect of the overpotential on CO electroreduction mechanisms on Cu(111): regulation and application of electrode potentials from a CO coverage-dependent electrochemical model.

A recently proposed CO coverage-dependent electrochemical model combined with the calculation of electronic structure is applied for the first time to study the effect of the overpotential on Cu-catalyzed CO electroreduction mechanisms by changing the coverage of surface adsorbed CO. The results show that the presently defined CH2O and CHOH pathways may be able to occur parallelly under different overpotentials. However, high overpotentials will facilitate CO electroreduction, thus explaining why a high overpotential is required during CO2 electroreduction in experiments on Cu electrodes. The potential-limiting step may be further CO electroreduction into CHO, which is considered as the origin of the experimentally observed high overpotentials. The analyses of electronic structure show that an adsorbed COδ- species is formed on the Cu electrodes, validating the previous experimental speculations on electron transfer between CO and Cu electrodes. More and more electrons are transferred into the π antibonding orbitals of the adsorbed CO with increasing surface CO coverage, leading to increasing overpotential and weaker and weaker CO bonding with the Cu surface. Thus, the significantly lower barrier of further CO electroreduction at higher overpotential can be correlated with lower CO adsorption energy. Interestingly, it is found that there is greater localization of electrons around the C than the O atom in the adsorbed CO molecule, explaining why the hydrated proton prefers to reach the C atom to form intermediate CHO rather than COH.

Mechanistic study on Cu-catalyzed CO2 electroreduction into CH4 at simulated low overpotentials based on an improved electrochemical model.

An improved CO coverage-dependent electrochemical model with explicit relaxed H2O molecules used in CO2 electroreduction is presented, which is firstly applied to Cu-catalyzed CO2 electroreduction into CH4 production at low overpotentials in this paper. The results show that the present defined CH2O and CHOH pathways via common intermediates CHO and CH2 may be able to occur parallelly at the present simulated low overpotential. The potential-limiting steps may be the formation of CO and its further electroreduction into CHO, which are considered as the origin of the observed experimentally high overpotential. The present study also explains why at electrochemical interfaces, only CH4 is observed experimentally on the Cu surface rather than CH3OH. The present results are found to be in excellent agreement with the available experimental data and partial theoretical analysis, further validating the rationality of the present employed methodology.

N-Acetylfarnesylcysteine is a novel class of peroxisome proliferator-activated receptor γ ligand with partial and full agonist activity in vitro and in vivo.

The thiazolidedione (TZD) class of drugs is clinically approved for the treatment of type 2 diabetes. The therapeutic actions of TZDs are mediated via activation of peroxisome proliferator-activated receptor γ (PPARγ). Despite their widespread use, concern exists regarding the safety of currently used TZDs. This has prompted the development of selective PPARγ modulators (SPPARMs), compounds that promote glucose homeostasis but with reduced side effects due to partial PPARγ agonism. However, this also results in partial agonism with respect to PPARγ target genes promoting glucose homeostasis. Using a gene expression-based screening approach we identified N-acetylfarnesylcysteine (AFC) as both a full and partial agonist depending on the PPARγ target gene (differential SPPARM). AFC activated PPARγ as effectively as rosiglitazone with regard to Adrp, Angptl4, and AdipoQ, but was a partial agonist of aP2, a PPARγ target gene associated with increased adiposity. Induction of adipogenesis by AFC was also attenuated compared with rosiglitazone. Reporter, ligand binding assays, and dynamic modeling demonstrate that AFC binds and activates PPARγ in a unique manner compared with other PPARγ ligands. Importantly, treatment of mice with AFC improved glucose tolerance similar to rosiglitazone, but AFC did not promote weight gain to the same extent. Finally, AFC had effects on adipose tissue remodeling similar to those of rosiglitazone and had enhanced antiinflammatory effects. In conclusion, we describe a new approach for the identification of differential SPPARMs and have identified AFC as a novel class of PPARγ ligand with both full and partial agonist activity in vitro and in vivo.

Theoretical insights into effect of surface composition of Pt-Ru bimetallic catalysts on CH3OH oxidation: mechanistic considerations.

A deeper mechanistic understanding on CH3OH oxidation on Pt-Ru alloys with different Ru surface compositions is provided by DFT-based theoretical studies in this paper. The present results show that alloying and surface compositions of Ru can change CH3OH oxidation pathway and activity. The optimal surface composition of Ru is speculated to be ca. 50% since the higher Ru surface composition can lead to formation of carbonaceous species that can poison surface. Our present calculated Ru surface composition of ca. 50% exhibits excellent consistency with experimental studies. The origin of enhanced catalytic activity of Pt-Ru alloys is determined. The significantly decreased surface work functions after alloying suggest more electrons are transferred into adsorbates. The calculated lower electrode potentials after alloying imply that lower overpotentials are required for CH3OH oxidation. The excellent consistency with experimental study on decreased onset potentials after alloying further confirms accuracy of our present calculated results. It is hoped that a systematic understanding of the atomic- and molecular-level processes on CH3OH oxidation mechanisms on Pt-Ru alloys will result in the ultimate goal of the explanation of origin of enhanced electrocatalytic activity and design of improved Pt-based alloy electrocatalysts for DMFCs.

Theoretical Insights into Potential-Dependent C-C Bond Formation Mechanisms during CO2 Electroreduction into C2 Products on Cu(100) at Simulated Electrochemical Interfaces.

An improved CO coverage-dependent electrochemical interface model with an explicit solvent effect on Cu(100) is presented in this paper, by which theoretical insights into the potential-dependent C-C bond formation pathways occurring in CO2 electrochemical reduction to C2 products can be obtained. Our present studies indicate that CHO is a crucial intermediate toward C1 products on Cu(111), and dimer OCCO is found to not be a viable species for the production of C2 products on Cu(100). The reaction pathway of CHO with CO and CHO dimerization into dimers COCHO and CHOCHO may be C-C bond formation mechanisms at low overpotential. However, at medium overpotential, C-C bond coupling takes place preferentially through the reaction of COH with CO species and COH dimerization into dimers COCOH and COHCOH. The formed dimers COCHO, CHOCOH, and CHOCHO via reactions of CHO with CO, COH, and CHO species may lead to C2 products, which are regarded as C-C bond formation mechanisms at high overpotential. The difference of obtained adsorption isotherms of CO on Cu(100) with that of Cu(111) may be able to explain the effect of the crystal face of Cu on product selectivity. The excellent consistencies between our present obtained conclusions and the available experimental reports and partial theoretical studies validate the reasonability of the present employed methodology, which can be also used to systematically study potential-dependent CO2 electroreduction pathways toward C2 products on Cu(100) or other metal catalysts.

Theoretical insights into the electroreduction mechanism of N2 to NH3 from an improved Au(111)/H2O interface model.

An improved H coverage-dependent Au(111)/H2O electrochemical interface model is proposed in this paper, which is firstly used to study electroreduction mechanisms of N2 into NH3 at the thermodynamical equilibrium potential in cooperation with electronic structure analysis. The results show that the associative mechanism is more favorable on Au(111) and therein alternating and distal pathways may be able to parallelly occur in gas phase and the present simulated electrochemical interface. The initial N2 reduction into the N2H intermediate is the rate determining step, which may be able to be regarded as the origin of the observed experimentally high overpotential during N2 electroreduction. The presence of an electrochemical environment can significantly change the N2 reduction pathway and decrease the barrier of the rate determining step, which can be ascribed to the significant electron accumulation and interaction between N2 molecules and H2O clusters. The theoretical results display excellent consistency with the available experimental data, confirming the rationality of the present proposed electrochemical model. The comparison of the barrier between the hydrogen evolution reaction and rate determining step well explains why the activity of Au electrodes is usually unsatisfactory. Accordingly, a single descriptor can be proposed, in which an ideal electrocatalyst should be able to reduce the barrier for initial N2 electroreduction into N2H. In this way, N2 electroreduction pathways can be facilitated and the yield of NH3 can be enhanced. We believe that the present study can represent progress to study N2 electroreduction mechanisms from an improved electrochemical model.

Potential-Dependent Competitive Electroreduction of CO2 into CO and Formate on Cu(111) from an Improved H Coverage-Dependent Electrochemical Model with Explicit Solvent Effect.

An improved density functional theory-based H coverage-dependent electrochemical model with explicit solvent effect is proposed for Cu(111), which is used to identify potential-dependent initial competitive CO2 electroreduction pathways considering HER. We find that a chemisorbed CO2 molecule at the present electrode/aqueous interface can be spontaneously formed and the overpotentials can affect its coordination pattern. The Eley-Rideal mechanism may be more favorable during the initial CO2 electroreduction into CO, whereas chemisorbed CO2 reacting with adsorbed H into HCOO- via the Langmuir-Hinshelwood mechanism is more facile to occur. The analyses of energetics suggest that the low overpotentials have a negligible influence on CO and HCOO- formation, and HCOO- species with monodentate and bidentate configurations may also parallelly form with the surmountable barriers at room temperature. However, the high potentials have an interruptive effect on initial CO2 electroreduction because of the significantly increased barriers, indicating that the chemisorbed CO2 can be stabilized by imposing more negative potentials and thus going against initial CO2 electroreduction. By analyzing the competing HER with initial CO2 electroreduction into CO, we find that HER is competitive with initial CO formation because of the required lower overpotentials. Simultaneously, the present study shows that the blocked Cu surface by adsorbed H and CO can explain why the initial CO formation pathway is unfavorable at the high overpotentials. Our present conclusions can also confirm the previous experimental report on initial formation of CO and HCOO-.

Density Functional Studies on Photophysical Properties of Boron-Pyridyl-Imino-Isoindoline Dyes: Effect of the Fusion.

In this work, to make out the aryl-fusion effect on the photophysical properties of boron-pyridyl-imino-isoindoline dyes, compounds 1-5 were theoretically studied through analyses of their geometric and electronic structures, optical properties, transport abilities, and radiative (k r) and non-radiative decay rate (k nr) constants. The highest occupied molecular orbitals of aryl-fused compounds 2-5 are higher owing to the extended conjugation. Interestingly, aryl fusion in pyridyl increases the lowest unoccupied molecular orbital (LUMO) level, while isoindoline decreases the LUMO level; thus, 4 and 5 with aryl fusion both in pyridyl and isoindoline exhibit a similar LUMO to 1. Compounds 4 and 5 show relatively low ionization potentials and high electron affinities, suggesting a better ability to inject holes and electrons. Importantly, the aryl fusion is conducive to the decrease of k IC. The designed compound 5 exhibits a red-shifted emission maximum, low λh, and low k IC, which endow it with great potential for applications in organic electronics. Our investigation provides an in-depth understanding of the aryl-fusion effect on boron-pyridyl-imino-isoindoline dyes at molecular levels and demonstrates that it is achievable.

Potential-Dependent CO2 Electroreduction Pathways on Cu(111) Based on an Improved Electrode/Aqueous Interface Model: Determination of the Origin of the Overpotentials.

Potential-dependent CO2 electroreduction pathways on Cu(111) are systematically studied with the aim of applying an improved electrode/aqueous interface model in this paper. The results indicate that our present defined CH2O and CHOH pathways may be able to parallelly take place at low overpotentials. Notably, the applied potentials will not alter the optimal CO2 reduction mechanisms. However, the presence of high overpotentials makes CO2 electroreduction more favorable, thus explaining why high overpotentials at experiments are required during CO2 electroreduction on Cu. Based on the potential-dependent energetics, the results suggest that COOH and CHO intermediates may be unstable at low overpotentials, in which COOH can easily change back to CO2 and CHO can easily change back to CO, thus preventing CO2 electroreduction. However, the high overpotentials will facilitate the formation and further electroreduction of CO and CHO. Thus, we can speculate that CO formation and then further electroreduction into CHO are the possible potential-limiting steps during CO2 electroreduction, which are regarded as the origin of experimentally observed high overpotentials. The present comprehensive understanding on CO2 electroreduction pathways can provide theoretical guidelines for efficiently designing Cu-based alloy electrocatalysts operated under the conditions of low overpotentials.

New Insights into the Pt-Catalyzed CH3OH Oxidation Mechanism: First-Principle Considerations on Thermodynamics, Kinetics, and Reversible Potentials.

A systematic first-principle study of CH3OH oxidation along indirect and direct pathways on Pt(111) has been carried out, and some new insights into CH3OH oxidation pathways in direct CH3OH fuel cells (DMFCs) are presented. The thermodynamics, kinetics, and reversible potentials for all possible elementary steps, initializing with C-H, O-H, and C-O bond cleavages and proceeding via sequential decomposition and oxidation from the reaction intermediates, are analyzed. Some key reactive intermediates are identified. By comparing the activation energies and reversible potentials of various possible elementary reaction steps, we can speculate that the initial CH3OH oxidation step proceeds by the CH3O intermediate under a nonelectrochemical environment, whereas it prefers to occur by the CH2OH intermediate under electrochemical environment. Furthermore, CHO hydroxylation into HCOOH along a direct pathway is more facile to occur than CHO dehydrogenation into CO along an indirect pathway at the nonelectrochemical interface, whereas the indirect and direct pathways may be parallel pathways on Pt(111) under the present simulated electrochemical environment. Simultaneously, CH3 can be easily formed through C-O bond cleavage in CH3OH, which is a nonelectrochemical step. Thus, the CH x (x = 0-3) species is possibly formed on Pt(111) during CH3OH oxidation regardless of being under an electrochemical or nonelectrochemical environment. The adsorbed CH x species will result in the blocking of the active sites and the prevention of further CH3OH oxidation. Our present findings on the formation of carbonaceous deposits on Pt(111) are consistent with the experimentally observed C-O bond scission of CH3OH into CH x species. Thus, we propose that the adsorbed residues that poisoned the Pt surface and impeded the performance of DMFCs may be CH x species, rather than CO species, since the direct pathway is more favorable on Pt(111) at the nonelectrochemical interface. However, the poisonous species that occupied the active sites of the Pt surface may be CH x and CO species due to the simultaneous occurrence of oxidation pathways on Pt(111) under the present simulated electrochemical environment. Based on the present study, some new insights into CH3OH oxidation mechanisms and designing strategies of Pt-based alloy catalysts for CH3OH oxidation can be provided.

Mechanistic insight into effect of doping of Ni on CO2 reduction on the (111) facet of Cu: thermodynamic and kinetic analyses of the elementary steps.

A systematic mechanistic investigation of CO2 reduction on a Ni-modified Cu(111) surface is performed based on an extensive set of density functional theory (DFT) calculations by focusing on the hydrocarbon CH4 formation pathways. By carefully analyzing reduction pathways on the Ni-modified Cu(111) surface, some important mechanistic information is deduced. The presence of Ni stabilizes all reaction intermediates, and thus reduces the activation barrier for almost all CO2 reduction steps. Most importantly, it can considerably lower than the activation barrier of CO2 hydrogenative dissociation into CO, which is the rate-determining step of CO2 reduction on a pure Cu(111) surface. Thus, the doping of Ni atom is able to activate CO2, leading to enhanced surface activity of CO2 reduction into hydrocarbons. Notably, the activation barriers that are required for CH4 and CH3OH formation are almost all easily overcome through the thermoactive process at ambient temperatures after doping of Ni atom. Thus, a higher CH4 and CH3OH yield may be expected in the presence of the doped Ni atom. Thermodynamic analyses indicate that doping of Ni may reduce the overpotential of CO formation through CO2 hydrogenative dissociation. On this basis, two decriptors may be proposed in order to describe the catalytic activity of Cu-based catalysts for CO2 reduction, and a perfect Cu-based alloy in CO2 reduction should moderately bind CO and form and reduce CO more easily. Simutaneously, CO hydrogenation occurs more easily on the (111) facet of Ni-modified Cu than dimerization, thereby the selectivity of (111) facet of Cu on production CH4 is further confirmed to some degree. The present study reveals a rich reaction chemistry and provides new insights to guide the rational design of Cu-based alloy catalysts for hydrocarbons formation from CO2 reduction. Graphical Abstract Reduction pathways of CO2 into hydrocarbonsᅟ.

New insights into the effects of alloying Pt with Ni on oxygen reduction reaction mechanisms in acid medium: a first-principles study.

The effects of alloying Pt with transition metal Ni on oxygen reduction reaction (ORR) mechanisms was investigated based on a systematic density functional theory (DFT) calculation explored in the present work. New insights into the ORR mechanisms were reported at the atomic level on Pt-segregated Pt3Ni(111). Only one molecular chemisorption state with the end-on OOH configuration was identified through geometry optimization and minimum energy path (MEP) analysis; top-bridge-top configuration as observed on pure Pt(111) was not identified on Pt-segregated Pt3Ni(111), indicating that alloying Pt with Ni influences the intermediates of ORR, and leads to only the dissociation mechanism of chemisorption state OOH species being involved in acid medium on Pt-segregated Pt3Ni(111). By contrast, the dissociation mechanisms of chemisorbed O2 molecule with top-bridge-top configuration and OOH species both were involved on pure Pt(111). The rds of the entire four-electron ORR was changed after Pt alloying with Ni. The rds of the entire ORR is the proton and electron transfer to O2 to form OOH on Pt-segregated Pt3Ni(111), whereas it is the reaction of O atom protonation to form OH species on pure Pt(111), indicating that sublayer Ni strongly influences the rds of ORR. The comparison of the ORR mechanisms explained that Pt3Ni alloy enhanced the ORR electrocatalytic activity more than pure Pt. The effect of electrode potential on ORR pathway on the pure Pt and Pt3Ni alloy was considered to obtain further insights into the electrochemical reduction of O2. Results showed that the proton and electron transfer becomes difficult at high potential. The ORR can easily proceed when the electrode potential lowers. For pure Pt- and Pt-based alloys, this phenomenon may imply the origin of the overpotential.

PGC1α promotes tumor growth by inducing gene expression programs supporting lipogenesis.

Despite the role of aerobic glycolysis in cancer, recent studies highlight the importance of the mitochondria and biosynthetic pathways as well. PPARγ coactivator 1α (PGC1α) is a key transcriptional regulator of several metabolic pathways including oxidative metabolism and lipogenesis. Initial studies suggested that PGC1α expression is reduced in tumors compared with adjacent normal tissue. Paradoxically, other studies show that PGC1α is associated with cancer cell proliferation. Therefore, the role of PGC1α in cancer and especially carcinogenesis is unclear. Using Pgc1α(-/-) and Pgc1α(+/+) mice, we show that loss of PGC1α protects mice from azoxymethane-induced colon carcinogenesis. Similarly, diethylnitrosamine-induced liver carcinogenesis is reduced in Pgc1α(-/-) mice as compared with Pgc1α(+/+) mice. Xenograft studies using gain and loss of PGC1α expression showed that PGC1α also promotes tumor growth. Interestingly, while PGC1α induced oxidative phosphorylation and tricarboxylic acid cycle gene expression, we also observed an increase in the expression of two genes required for de novo fatty acid synthesis, ACC and FASN. In addition, SLC25A1 and ACLY, which are required for the conversion of glucose into acetyl-CoA for fatty acid synthesis, were also increased by PGC1α, thus linking the oxidative and lipogenic functions of PGC1α. Indeed, using stable (13)C isotope tracer analysis, we show that PGC1α increased de novo lipogenesis. Importantly, inhibition of fatty acid synthesis blunted these progrowth effects of PGC1α. In conclusion, these studies show for the first time that loss of PGC1α protects against carcinogenesis and that PGC1α coordinately regulates mitochondrial and fatty acid metabolism to promote tumor growth.

Activation of the AMP-activated protein kinase-p38 MAP kinase pathway mediates apoptosis induced by conjugated linoleic acid in p53-mutant mouse mammary tumor cells.

Conjugated linoleic acid (CLA) inhibits tumorigenesis and tumor growth in most model systems, an effect mediated in part by its pro-apoptotic activity. We previously showed that trans-10,cis-12 CLA induced apoptosis of p53-mutant TM4t mouse mammary tumor cells through both mitochondrial and endoplasmic reticulum stress pathways. In the current study, we investigated the role of AMP-activated protein kinase (AMPK), a key player in fatty acid metabolism, in CLA-induced apoptosis in TM4t cells. We found that t10,c12-CLA increased phosphorylation of AMPK, and that CLA-induced apoptosis was enhanced by the AMPK agonist 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) and inhibited by the AMPK inhibitor compound C. The increased AMPK activity was not due to nutrient/energy depletion since ATP levels did not change in CLA-treated cells, and knockdown of the upstream kinase LKB1 did not affect its activity. Furthermore, our data do not demonstrate a role for the AMPK-modulated mTOR pathway in CLA-induced apoptosis. Although CLA decreased mTOR levels, activity was only modestly decreased. Moreover, rapamycin, which completely blocked the activity of mTORC1 and mTORC2, did not induce apoptosis, and attenuated rather than enhanced CLA-induced apoptosis. Instead, the data suggest that CLA-induced apoptosis is mediated by the AMPK-p38 MAPK-Bim pathway: CLA-induced phosphorylation of AMPK and p38 MAPK, and increased expression of Bim, occurred with a similar time course as apoptosis; phosphorylation of p38 MAPK was blocked by compound C; the increased Bim expression was blocked by p38 MAPK siRNA; CLA-induced apoptosis was attenuated by the p38 inhibitor SB-203580 and by siRNAs directed against p38 MAPK or Bim.

Apoptosis induced by t10,c12-conjugated linoleic acid is mediated by an atypical endoplasmic reticulum stress response.

Conjugated linoleic acid (CLA) inhibits rat mammary carcinogenesis, in part by inducing apoptosis of preneoplastic and neoplastic mammary epithelial cells. The current study focused on the mechanism by which apoptosis is induced. In TM4t mammary tumor cells, trans-10,cis-12 (t10,c12)-CLA induced proapoptotic C/EBP-homologous protein (CHOP) concurrent with the cleavage of poly(ADP-ribose) polymerase. Knockdown of CHOP attenuated t10,c12-CLA-induced apoptosis. Furthermore, t10,c12-CLA induced the cleavage of endoplasmic reticulum (ER)-resident caspase-12, and a selective inhibitor of caspase-12 significantly alleviated t10,c12-CLA-induced apoptosis. Using electron microscopy, we observed that t10,c12-CLA treatment resulted in marked dilatation of the ER lumen. Together, these data suggest that t10,c12-CLA induces apoptosis through ER stress. To further explore the ER stress pathway, we examined the expression of the following upstream ER stress signature markers in response to CLA treatment: X-box binding protein 1 (XBP1) mRNA (unspliced and spliced), phospho-eukaryotic initiation factor (eIF) 2 alpha, activating transcription factor 4 (ATF4), and BiP proteins. We found that t10,c12-CLA induced the expression and splicing of XBP1 mRNA as well as the phosphorylation of eIF2 alpha. In contrast, ATF4 was induced modestly, but not significantly, and BiP was not altered. In summary, our data demonstrate that apoptosis induced by t10,c12-CLA is mediated, at least in part, through an atypical ER stress response that culminates in the induction of CHOP and the cleavage of caspase-12.