Press Forming Process of Closed-profile Automotive Parts Without Flange

AbstractAutomobiles are required weight reduction and improvement of collision safety. Additionally, rigidity of vehicle bodies is important performance that affects driving stability. Collision safety and rigidity of vehicles are strongly affected by strength and rigidity of the structural components. Accordingly, they are made of high strength steel / ultra-high strength steel and have closed cross section shapes (closed-profiles). Conventional closed-profile components are currently assembled by spot welding of two press-formed parts. Flanges of press-formed parts are required for spot welding and inhibit weight reduction. In the present situation, a new forming method was developed for closed-profile parts without flanges. The developed method was constituted three forming processes by using conventional mechanical press machines. In the 1st process, a steel sheet was partially stretched for adjustment of the cross section length and formed folds at ridgeline positions of the final shape. In the 2nd process, the formed sheet in 1st process was bent by press forming. In the 3rd process, the formed sheet in 2nd process was closed to hexagonal cross section shape by side tools which were driven transversely by cams. And finally it was added compression in plain by the punch. Trial product by the developed forming method satisfied the target performances (bending and torsion rigidity and collision strength). Weight reduction ratio was 39% by optimization of the cress section shape and removing flanges

Evaluation of 147 Kampo prescriptions as novel protein tyrosine phosphatase 1B (PTP1B) inhibitory agents

BACKGROUND: Protein tyrosine phosphatase (PTP) 1B, a negative regulator of the insulin and leptin signaling pathways, is currently considered a promising target for the development of novel therapeutic approaches used to treat insulin-resistant type 2 diabetes mellitus (IR-T2DM). In this study, we examined the PTP1B inhibitory activity of 147 Japanese prescription Kampo formulations to evaluate their potential for clinical application in IR-T2DM treatment. METHODS: We specifically defined the prescribed daily dose as 1 Unit (U), and 147 Japanese prescription Kampo formulations were screened for PTP1B inhibitory activity at a final concentration of 0.1 mU/mL. We investigated the dependence of the inhibitory activity on the concentration of the Kampo formulations that exhibited high PTP1B inhibitory activity. Their inhibition mode by kinetic analysis, inhibitory selectivities against four homologous PTPs (TCPTP, VHR, SHP-1 and SHP-2) and cellular activity in the insulin-signaling pathway by increasing the insulin-stimulated Akt phosphorylation level in human hepatocellular liver carcinoma HepG2 cells, were also investigated. The statistical partial least squares regression method was used to identify the crude drugs with the greatest contribution to the PTP1B inhibitory activity of the Kampo formulations. RESULTS: Daiokanzoto, Masiningan, Tokakujokito, Keimakakuhanto and Choijokito exhibited high PTP1B inhibitory activity, which was concentration-dependent. Daiokanzoto, Masiningan and Tokakujokito inhibited PTP1B by mixed inhibition modes and exhibited different inhibitory selectivities against four homologous PTPs. Masiningan also exhibited cellular activity. Statistical analyses indicated that the constituent crude drug Rhei Rhizoma provided the greatest contribution to the PTP1B inhibitory activity of these Kampo formulations. CONCLUSIONS: High PTP1B inhibitory activity was predominantly associated with formulations that were classified as Jyokito in Kampo medicine and with a modern clinical indication of constipation. Currently, there is no clinical treatment for IR-T2DM that uses a mechanism of action based on PTP1B inhibition. Thus, we propose the Kampo formulations identified in this study as strong PTP1B inhibitors, which could be developed as clinical therapeutic agents to treat IR-T2DM

Human plasma N-glycosylation as analyzed by MALDI-FTICR-MS associates with markers of inflammation and metabolic health

Glycosylation is an abundant co- and post-translational protein modification of importance to protein processing and activity. While not template-defined, glycosylation does reflect the biological state of an organism and is a high-potential biomarker for disease and patient stratification. However, to interpret a complex but informative sample like the total plasma N-glycome (TPNG), it is important to establish its baseline association with plasma protein levels and systemic processes. Thus far, large scale studies (n > 200) of the TPNG have been performed with methods of chromatographic and electrophoretic separation, which, while being informative, are limited in resolving the structural complexity of plasma N-glycans. Mass spectrometry (MS) has the opportunity to contribute additional information on, among others, antennarity, sialylation, and the identity of high-mannose type species. Here, we have used matrix-assisted laser desorption/ionization (MALDI)-Fourier transform ion cyclotron resonance (FTICR)- MS to study the TPNGs of 2,144 healthy middle-aged individuals from the Leiden Longevity Study, to allow association analysis with markers of metabolic health and inflammation. To achieve this, N-glycans were enzymatically released from their protein backbones, labeled at the reducing end with 2-aminobenzoic acid, and following purification analyzed by negative ion mode intermediate pressure MALDI-FTICR-MS. In doing so, we achieved the relative quantification of 61 glycan compositions, ranging from Hex4HexNAc2 to Hex7HexNAc6dHex1Neu5Ac4, as well as that of 39 glycosylation traits derived thereof. Next to confirming known associations of glycosylation with age and sex by MALDI-FTICR-MS, we report novel associations with C-reactive protein (CRP), interleukin 6 (IL-6), body mass index (BMI), leptin, adiponectin, HDL cholesterol, triglycerides (TG), insulin, gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT) and smoking. Overall, the bisection, galactosylation and sialylation of diantennary species, the sialylation of tetraantennary species, and the size of high-mannose species proved to be important plasma characteristics associated with inflammation and metabolic health

A Semi-Physiologically Based Pharmacokinetic Model Describing the Altered Metabolism of Midazolam Due to Inflammation in Mice

This is the author's accepted manuscript.Purpose To investigate influence of inflammation on metabolism and pharmacokinetics (PK) of midazolam (MDZ) and construct a semi-physiologically based pharmacokinetic (PBPK) model to predict PK in mice with inflammatory disease. Methods Glucose-6-phosphate isomerase (GPI)-mediated inflammation was used as a preclinical model of arthritis in DBA/1 mice. CYP3A substrate MDZ was selected to study changes in metabolism and PK during the inflammation. The semi-PBPK model was constructed using mouse physiological parameters, liver microsome metabolism, and healthy animal PK data. In addition, serum cytokine, and liver-CYP (cytochrome P450 enzymes) mRNA levels were examined. Results The in vitro metabolite formation rate was suppressed in liver microsomes prepared from the GPI-treated mice as compared to the healthy mice. Further, clearance of MDZ was reduced during inflammation as compared to the healthy group. Finally, the semi-PBPK model was used to predict PK of MDZ after GPI-mediated inflammation. IL-6 and TNF-α levels were elevated and liver-cyp3a11 mRNA was reduced after GPI treatment. Conclusion The semi-PBPK model successfully predicted PK parameters of MDZ in the disease state. The model may be applied to predict PK of other drugs under disease conditions using healthy animal PK and liver microsomal data as inputs

Genomics Meets Glycomics—The First GWAS Study of Human N-Glycome Identifies HNF1α as a Master Regulator of Plasma Protein Fucosylation

Over half of all proteins are glycosylated, and alterations in glycosylation have been observed in numerous physiological and pathological processes. Attached glycans significantly affect protein function; but, contrary to polypeptides, they are not directly encoded by genes, and the complex processes that regulate their assembly are poorly understood. A novel approach combining genome-wide association and high-throughput glycomics analysis of 2,705 individuals in three population cohorts showed that common variants in the Hepatocyte Nuclear Factor 1α (HNF1α) and fucosyltransferase genes FUT6 and FUT8 influence N-glycan levels in human plasma. We show that HNF1α and its downstream target HNF4α regulate the expression of key fucosyltransferase and fucose biosynthesis genes. Moreover, we show that HNF1α is both necessary and sufficient to drive the expression of these genes in hepatic cells. These results reveal a new role for HNF1α as a master transcriptional regulator of multiple stages in the fucosylation process. This mechanism has implications for the regulation of immunity, embryonic development, and protein folding, as well as for our understanding of the molecular mechanisms underlying cancer, coronary heart disease, and metabolic and inflammatory disorders

Early- and advanced non-enzymatic glycation in diabetic vascular complications: the search for therapeutics

Cardiovascular disease is a common complication of diabetes and the leading cause of death among people with diabetes. Because of the huge premature morbidity and mortality associated with diabetes, prevention of vascular complications is a key issue. Although the exact mechanism by which vascular damage occurs in diabetes in not fully understood, numerous studies support the hypothesis of a causal relationship of non-enzymatic glycation with vascular complications. In this review, data which point to an important role of Amadori-modified glycated proteins and advanced glycation endproducts in vascular disease are surveyed. Because of the potential role of early- and advanced non-enzymatic glycation in vascular complications, we also described recent developments of pharmacological inhibitors that inhibit the formation of these glycated products or the biological consequences of glycation and thereby retard the development of vascular complications in diabetes