Recombinant human PDCD5 (rhPDCD5) protein is protective in a mouse model of multiple sclerosis.

BackgroundIn multiple sclerosis (MS) and its widely used animal model, experimental autoimmune encephalomyelitis (EAE), autoreactive T cells contribute importantly to central nervous system (CNS) tissue damage and disease progression. Promoting apoptosis of autoreactive T cells may help eliminate cells responsible for inflammation and may delay disease progression and decrease the frequency and severity of relapse. Programmed cell death 5 (PDCD5) is a protein known to accelerate apoptosis in response to various stimuli. However, the effects of recombinant human PDCD5 (rhPDCD5) on encephalitogenic T cell-mediated inflammation remain unknown.MethodsWe examined the effects of intraperitoneal injection of rhPDCD5 (10 mg/kg) on EAE both prophylactically (started on day 0 post-EAE induction) and therapeutically (started on the onset of EAE disease at day 8), with both of the treatment paradigms being given every other day until day 25. Repeated measures two-way analysis of variance was used for statistical analysis.ResultsWe showed that the anti-inflammatory effects of rhPDCD5 were due to a decrease in Th1/Th17 cell frequency, accompanied by a reduction of proinflammatory cytokines, including IFN-γ and IL-17A, and were observed in both prophylactic and therapeutic regimens of rhPDCD5 treatment in EAE mice. Moreover, rhPDCD5-induced apoptosis of myelin-reactive CD4+ T cells, along with the upregulation of Bax and downregulation of Bcl-2, and with activated caspase 3.ConclusionsOur data demonstrate that rhPDCD5 ameliorates the autoimmune CNS disease by inhibiting Th1/Th17 differentiation and inducing apoptosis of predominantly pathogenic T cells. This study provides a novel mechanism to explain the effects of rhPDCD5 on neural inflammation. The work represents a translational demonstration that rhPDCD5 has prophylactic and therapeutic properties in a model of multiple sclerosis

Multi-objective optimization design for a battery pack of electric vehicle with surrogate models

In this investigation, a systematic surrogate-based optimization design framework for a battery pack is presented. An air-cooling battery pack equipped on electric vehicles is first designed. Finite element analysis (FEA) results of the baseline design show that global maximum stresses under x-axis and y-axis transient acceleration shock condition are both above the tensile limit of material. Selecting the panel and beam thickness of battery pack as design variables, with global maximum stress constraints in shock cases, a multi-objective optimization problem is implemented using metamodel technique and multi-objective particle-swarm-optimization (MOPSO) algorithm to simultaneously minimize the total mass and maximize the restrained basic frequency. It is found that 2nd order polynomial response surface (PRS), 3rd order PRS and radial basis function (RBF) are the most accurate and appropriate metamodels for restrained basic frequency, global maximum stresses under x-axis and y-axis shock conditions respectively. Results demonstrate that all the optimal solutions in Pareto Frontier have heavier weight and lower frequency compared with baseline design due to the restriction of global maximum stress response. Finally, two optimal schemes, “Knee Point” and “lightest weight”, satisfied both of the stress constraint conditions, show great consistency with FEA results and can be selected as alternative improved schemes

Flavonoids activate pregnane × receptor-mediated CYP3A4 gene expression by inhibiting cyclin-dependent kinases in HepG2 liver carcinoma cells

<p>Abstract</p> <p>Background</p> <p>The expression of the drug-metabolizing enzyme cytochrome P450 3A4 (CYP3A4) is regulated by the pregnane × receptor (PXR), which is modulated by numerous signaling pathways, including the cyclin-dependent kinase (Cdk) pathway. Flavonoids, commonly consumed by humans as dietary constituents, have been shown to modulate various signaling pathways (e.g., inhibiting Cdks). Flavonoids have also been shown to induce <it>CYPs </it>expression, but the underlying mechanism of action is unknown. Here, we report the mechanism responsible for flavonoid-mediated PXR activation and <it>CYP </it>expression.</p> <p>Results</p> <p>In a cell-based screen designed to identify compounds that activate PXR-mediated <it>CYP3A4 </it>gene expression in HepG2 human carcinoma cells, we identified several flavonoids, such as luteolin and apigenin, as PXR activators. The flavonoids did not directly bind to PXR, suggesting that an alternative mechanism may be responsible for flavonoid-mediated PXR activation. Consistent with the Cdk5-inhibitory effect of flavonoids, Cdk5 and p35 (a non-cyclin regulatory subunit required to activate Cdk5) were expressed in HepG2. The activation of Cdk5 attenuated PXR-mediated <it>CYP3A4 </it>expression whereas its downregulation enhanced it. The Cdk5-mediated downregulation of <it>CYP3A4 </it>promoter activity was restored by flavonoids, suggesting that flavonoids activate PXR by inactivating Cdk5. <it>In vitro </it>kinase assays showed that Cdk5 directly phosphorylates PXR. The Cdk kinase profiling assay showed that apigenin inhibits multiple Cdks, suggesting that several Cdks may be involved in activation of PXR by flavonoids.</p> <p>Conclusions</p> <p>Our results for the first time link the stimulatory effect of flavonoids on <it>CYP </it>expression to their inhibitory effect on Cdks, through a PXR-mediated mechanism. These results may have important implications on the pharmacokinetics of drugs co-administered with herbal remedy and herbal-drug interactions.</p