Long-Term Efficacy and Safety of Human Umbilical Cord Mesenchymal Stromal Cells in Rotenone-Induced Hemiparkinsonian Rats

Several studies have shown functional improvements, neuroprotective, and neuroregenerative effects after mesenchymal stem cells transplantation to parkinsonian animal models. However, questions remain about the safety, feasibility, and long-term efficacy of this approach. In this study, we investigated migration, therapeutic, tumorigenesis, and epileptogenic effects of human umbilical cord mesenchymal stromal cells (HUMSCs) 1 year after transplantation into rotenone-induced hemiparkinsonian rats. Our data indicated that DiI-labeled HUMSCs migrated in the lesioned hemisphere, from corpus striatum (CPu) to substantia nigra. By integrating with host cells and differentiating into NSE, GFAP, Nestin, and tyrosine hydroxylase-positive cells, HUMSCs prevented 48.4% dopamine neurons from degeneration and 56.9% dopamine terminals from loss, both correlating with improvement of apomorphine-induced rotations. The CD50 and CD97 value of pentylenetetrazol and semiquantitative immunohistochemical analysis of proliferating cell nuclear antigen (PCNA), β-catenin, C-myc, and NF-κB expression showed no significant difference between HUMSCs transplanted and untransplanted groups, whereas the expressions of Bcl-2 and P53 in the grafted CPu were upregulated by 281% and 200% compared to ungrafted CPu. The results of this long-term study suggest that HUMSCs transplantation, 1 of the most potential treatments for Parkinson's disease, is an effective and safe approach

Edaravone Guards Dopamine Neurons in a Rotenone Model for Parkinson's Disease

3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone), an effective free radical scavenger, provides neuroprotection in stroke models and patients. In this study, we investigated its neuroprotective effects in a chronic rotenone rat model for Parkinson's disease. Here we showed that a five-week treatment with edaravone abolished rotenone's activity to induce catalepsy, damage mitochondria and degenerate dopamine neurons in the midbrain of rotenone-treated rats. This abolishment was attributable at least partly to edaravone's inhibition of rotenone-induced reactive oxygen species production or apoptotic promoter Bax expression and its up-regulation of the vesicular monoamine transporter 2 (VMAT2) expression. Collectively, edaravone may provide novel clinical therapeutics for PD

Stereotaxical Infusion of Rotenone: A Reliable Rodent Model for Parkinson's Disease

A clinically-related animal model of Parkinson's disease (PD) may enable the elucidation of the etiology of the disease and assist the development of medications. However, none of the current neurotoxin-based models recapitulates the main clinical features of the disease or the pathological hallmarks, such as dopamine (DA) neuron specificity of degeneration and Lewy body formation, which limits the use of these models in PD research. To overcome these limitations, we developed a rat model by stereotaxically (ST) infusing small doses of the mitochondrial complex-I inhibitor, rotenone, into two brain sites: the right ventral tegmental area and the substantia nigra. Four weeks after ST rotenone administration, tyrosine hydroxylase (TH) immunoreactivity in the infusion side decreased by 43.7%, in contrast to a 75.8% decrease observed in rats treated systemically with rotenone (SYS). The rotenone infusion also reduced the DA content, the glutathione and superoxide dismutase activities, and induced alpha-synuclein expression, when compared to the contralateral side. This ST model displays neither peripheral toxicity or mortality and has a high success rate. This rotenone-based ST model thus recapitulates the slow and specific loss of DA neurons and better mimics the clinical features of idiopathic PD, representing a reliable and more clinically-related model for PD research

Do environmental subsidies spur environmental innovation? Empirical evidence from Chinese listed firms

Although one of the main reasons why governments offer environmental subsidies to firms is to encourage environmental innovation, the effectiveness of such measures is unclear. In this study, we examine the effects of subsidies on firms’ environmental innovation activities (i.e. environmental technology innovations and environmental management innovations). We use fine-grained panel data on Chinese listed manufacturing companies over the period 2011–2015. We find that whilst Chinese government environmental subsidies boost firms’ environmental management innovation significantly, their effect on environmental technology innovations is not statistically significant. We employ an instrumental variable two-stage least squares (IV-2SLS) approach to handle potential selection bias. We find also that there is no statistically significant relationship between firms’ environmental management innovations and environmental technology innovations. These findings hold for a range of robustness tests

Ni-Doping Effects on Carbon Diffusion and Oxidation over Mo₂C Surfaces

Spin-polarized periodic density functional theory calculations have been performed to study the adsorption, diffusion, and oxidation of carbon on the Mo-terminated β-Mo₂C­(001) surface as well as on a model Ni-doped β-Mo₂C­(001) surface with a surface Ni:Mo ratio of 1:2. The most stable adsorption sites for O and CO were found to be similar on the two surfaces, whereas those for C are different in that C prefers to adsorb at the step interface on the model Ni-doped surface. The adsorption energies for all three species were found to be less negative on the Ni-doped surface. The energy barriers and reaction energies for the diffusion and oxidation of carbon on the above β-Mo₂C­(001) surfaces were calculated. On the pure β-Mo₂C­(001) surface, C diffusion from its most stable adsorption site has a much smaller energy barrier of ∼1.0 eV than C oxidation of ∼2.6 eV, with both processes being quite endothermic. Upon Ni doping, the lowest energy barrier for C diffusion from its most stable adsorption site remains ∼1.0 eV, whereas the lowest energy barrier for C oxidation is ∼1.6 eV, much lower than that of ∼2.6 eV on the pure β-Mo₂C­(001) surface. The energy barrier difference between C diffusion and oxidation of ∼0.6 eV on the Ni-doped surface is much smaller than that of ∼1.6 eV on the pure β-Mo₂C­(001) surface, and this can be beneficial for preventing carbon deposition and increasing CO selectivity

CO Dissociation Mechanism on Cu-Doped Fe(100) Surfaces

Periodic density functional theory calculations were carried out to investigate CO dissociation pathways on the Fe(100) surfaces covered with up to one monolayer of Cu atoms, which serve as the simple models for the Cu/Fe catalysts for higher alcohol synthesis (HAS) from syngas. For all the model catalyst surfaces, H-assisted CO dissociation was predicted to have lower energy barriers than direct CO dissociation. The difference in the energy barriers between the two dissociation pathways increases as Cu surface coverage increases, suggesting reduced contribution of direct CO dissociation on Cu-rich surfaces. A further thermodynamic analysis also reaches the same conclusion. Several reaction properties for CO dissociation, including CO physisorption and chemisorption energies, and energy barriers for direct and H-assisted CO dissociations, were found to scale linearly with Cu surface coverage, and these reaction properties were predicted to depend largely on the structure of the surface layer, which can be expected to also apply to other metal alloy catalysts. Cu doping was found to reduce the activity of the Fe­(100) surface in catalyzing direct and H-assisted CO dissociations, so CO dissociations should occur primarily on Fe-rich surfaces, leading to CH_<i>x</i> formation, whereas Cu-rich surfaces are potential sources for physisorbed CO molecules. This is also expected to apply to other Cu/M catalysts and is consistent with the dual site mechanism previously proposed for these bimetallic catalysts. A synergy between these two types of active sites is beneficial for the formation of higher alcohols, which may be the reason for the superior performance of the Cu/Fe catalysts for the HAS reaction

Methane Activations by Lanthanum Oxide Clusters

Density functional theory and coupled cluster theory were employed to study the activations of CH₄ by neutral lanthanum oxide clusters (LaO­(OH), La₂O₃, La₃O₄(OH), La₄O₆, La₆O₉) as models for the La₂O₃ catalysts for the oxidative coupling of methane (OCM) reaction. The physisorption energies (Δ<i>H</i>_298 K) of CH₄ on the lanthanum oxide clusters were predicted to be −4 to −3 kcal/mol at the CCSD­(T) level. CH₄ is activated by hydrogen transfer to one of the O sites on the lanthanum oxide clusters, and the energy barriers (Δ<i>E</i>_0 K) from the physisorption structures were calculated to be modest at ∼20 kcal/mol for La₂O₃ and ∼25 kcal/mol for the other clusters. This is accompanied by the formation of a La–CH₃ bond, whose bond dissociation energy (Δ<i>E</i>_0 K) was calculated to be 53 to 60 kcal/mol. CH₄ chemisorption is slightly exothermic on LaO­(OH) and La₂O₃, whereas it becomes increasingly endothermic for the larger lanthanum oxide clusters. The formation of the CH₃ radical was predicted to be substantially endothermic, by ∼50 kcal/mol for LaO­(OH) and La₂O₃ and 64 to 76 kcal/mol for La₃O₄(OH) and La₄O₆ (Δ<i>H</i>_298 K). Calculations on the activation of CH₄ by La₆O₉ with a higher coordination number for both the La and O sites than La₄O₆ yield an energy barrier slightly higher by <1 kcal/mol, suggesting that the effects of the coordination numbers on the reaction energetics are rather small. The energy barrier for hydrogen abstraction does not correlate well with the negative charge on the O site, and a linear relation between the energy barrier and the chemisorption energy was not found for all the lanthanum oxide clusters, which is attributed to the strong dependency of their correlation on the specific chemical environment of the reactive site. Cluster reaction energies, physisorption and chemisorption energies, energy barriers, and La–CH₃ bond energies calculated at the DFT level with the B3LYP and PBE functionals were compared with those calculated at the CCSD­(T) level showing that the B3LYP functional yields better cluster reaction energies, chemisorption energies, and energy barriers. Although the PBE functional yields better physisorption energies, the DFT results can deviate substantially from the CCSD­(T) values. Although the O^2– sites in these cluster models were predicted to be less reactive toward CH₄ than the O^– sites modeled by the nonstoichiometric La₂O_3.33(001) surface (Palmer, M. S. et al. <i>J. Am. Chem. Soc.</i> <b>2002</b>, <i>124</i>, 8452), they are more reactive than the O₂^2– site modeled on the stoichiometric La₂O₃(001) surface, which suggests the relevance of the lattice oxygen sites on the La₂O₃ catalyst surfaces in the OCM reaction

Tau phosphorylation and μ-calpain activation mediate the dexamethasone-induced inhibition on the insulin-stimulated Akt phosphorylation.

Evidence has suggested that insulin resistance (IR) or high levels of glucocorticoids (GCs) may be linked with the pathogenesis and/or progression of Alzheimer's disease (AD). Although studies have shown that a high level of GCs results in IR, little is known about the molecular details that link GCs and IR in the context of AD. Abnormal phosphorylation of tau and activation of μ-calpain are two key events in the pathology of AD. Importantly, these two events are also related with GCs and IR. We therefore speculate that tau phosphorylation and μ-calpain activation may mediate the GCs-induced IR. Akt phosphorylation at Ser-473 (pAkt) is commonly used as a marker for assessing IR. We employed two cell lines, wild-type HEK293 cells and HEK293 cells stably expressing the longest human tau isoform (tau-441; HEK293/tau441 cells). We examined whether DEX, a synthetic GCs, induces tau phosphorylation and μ-calpain activation. If so, we examined whether the DEX-induced tau phosphorylation and μ-calpain activation mediate the DEX-induced inhibition on the insulin-stimulated Akt phosphorylation. The results showed that DEX increased tau phosphorylation and induced tau-mediated μ-calpain activation. Furthermore, pre-treatment with LiCl prevented the effects of DEX on tau phosphorylation and μ-calpain activation. Finally, both LiCl pre-treatment and calpain inhibition prevented the DEX-induced inhibition on the insulin-stimulated Akt phosphorylation. In conclusion, our study suggests that the tau phosphorylation and μ-calpain activation mediate the DEX-induced inhibition on the insulin-stimulated Akt phosphorylation