Selective Inhibition of Bakuchicin Isolated from Psoralea corylifolia on CYP1A in Human Liver Microsomes

Bakuchicin is a furanocoumarin isolated from Psoralea corylifolia and shows several biological activities. Although there have been studies on the biological effects of bakuchicin, its modulation potency of CYP activities has not been previously investigated. Here, we investigated the inhibitory effects of bakuchicin on the activities of CYP isoforms by using a cocktail of probe substrates in pooled human liver microsomes (HLMs) and human recombinant cDNA-expressed CYP. Bakuchicin strongly inhibited CYP1A-mediated phenacetin O-deethylation with an IC 50 value of 0.43 M in HLMs. It was confirmed by human recombinant cDNA-expressed CYP1A1 and CYP1A2 with a value of 0.11 M and 0.32 M, respectively. A Lineweaver-Burk plot indicated that the inhibition mechanism of bakuchicin was competitive inhibition. Overall, this is the first study to investigate the potential CYP1A1 and CYP1A2 inhibition associated with bakuchicin and to report its competitive inhibitory effects on HLMs

Volumetric change of the latissimus dorsi muscle after immediate breast reconstruction with an extended latissimus dorsi musculocutaneous flap

Background In immediate breast reconstruction using an extended latissimus dorsi musculocutaneous (eLDMC) flap, the volume of the flap decreases, which causes a secondary deformity of the breast shape. Since little research has investigated this decrease in muscle volume, the authors conducted an objective study to characterize the decrease in muscle volume after breast reconstruction using an eLDMC flap. Methods Research was conducted from October 2011 to November 2016. The subjects included 23 patients who underwent mastectomy due to breast cancer, received immediate reconstruction using an eLDMC flap without any adjuvant chemotherapy or radiotherapy, and received a computed tomography (CT) scan from days 7 to 10 after surgery and 6 to 8 months postoperatively. In 10 patients, an additional CT scan was conducted 18 months postoperatively. Axial CT scans were utilized to measure the volumetric change of the latissimus dorsi muscle during the follow-up period. Results In the 23 patients, an average decrease of 54.5% was observed in the latissimus dorsi muscle volume between the images obtained immediately postoperatively and the scans obtained 6 to 8 months after surgery. Ten patients showed an average additional decrease of 11.9% from 6–8 months to 18 months after surgery. Conclusions We studied changes in the volume of the latissimus dorsi muscle after surgery using an eLDMC flap performed after a mastectomy without adjuvant chemotherapy or radiotherapy. In this study, we found that immediate breast reconstruction using a latissimus dorsi muscle flap led to a decrease in muscle volume of up to 50%

Investigation of the dorsolateral branch of the posterior intercostal artery for use as the pedicle of a free flap: A cadaveric study and case series

Background The dorsolateral branch of the posterior intercostal artery (DLBPI) can be easily found while harvesting a latissimus dorsi (LD) musculocutaneous flap for breast reconstruction. However, it remains unknown whether this branch can be used for a free flap and whether this branch alone can provide perfusion to the skin. We examined whether the DLBPI could be reliably found and whether it could provide sufficient perfusion. Methods We dissected 10 fresh cadavers and counted DLBPIs with a diameter larger than 2 mm. For each DLBPI, the following parameters were measured: distance from the lateral margin of the LD muscle, level of the intercostal space, distance from the spinal process, and distance from the inferior angle of the scapula. Results The DLBPI was easily found in all cadavers and was reliably located in the specified area. The average number of DLBPIs was 1.65. They were located between the seventh and eleventh intercostal spaces. The average length of the DLBPI between the intercostal space and the LD muscle was 4.82 cm. To assess the perfusion of the DLBPIs, a lead oxide mixture was injected through the branch and observed using X-rays, and it showed good perfusion. Conclusions The DLBPI can be used as a pedicle in free flaps for small defects. DLBPI flaps have some limitations, such as a short pedicle. However, an advantage of this branch is that it can be reliably located through simple dissection. For women, it has the advantage of concealing the donor scar underneath the bra band

Meta-analysis of the Association between HLA-DRB1 Allele and Rheumatoid Arthritis Susceptibility in Asian Populations

The aims of this study were to summarize results on the association of HLA-DRB1 with rheumatoid arthritis (RA) in Asians and to determine if the shared epitope (SE) hypothesis could explain the meta-analysis results. Among the papers published between January 1987 and July 2006 on RA susceptibility in Asian-Mongoloid populations (Korean, Japanese, Chinese, and Thai), 12 were selected for the meta-analysis. Mongoloid-Asian patients with RA had significantly higher frequencies of HLA-DRB1*0101, *0401, *0410, and *1001 than controls (OR 1.5-2.1, p<0.05 for association). When analyses were restricted to more ethnically homogeneous populations, HLA-DRB1*0405 showed a significant susceptibility to RA in Koreans (OR 5.65, 95% CI 4.32-7.39), whereas the HLA-DRB1*0301, *0403, *0406, *0701, *1301, and *1405 alleles showed protective association with RA (OR 0.32-0.70, p<0.05 for association). In conclusion, it was found that HLA-DRB1 *0101, *0401, *0405, *0410, and *1001 are susceptible, while HLA-DRB1*0301, *0403, *0406, *0701, *1301, and *1405 are protective in Asian-Mongoloids. All the RA-associated alleles except DRB1*0301 could be explained by the structural model supporting the SE hypothesis that RA susceptibility is determined by the combination of amino acid residues at HLA-DR β71 and β74, not by β71 alone

Selective Inhibition of Bakuchicin Isolated from Psoralea corylifolia on CYP1A in Human Liver Microsomes

Bakuchicin is a furanocoumarin isolated from Psoralea corylifolia and shows several biological activities. Although there have been studies on the biological effects of bakuchicin, its modulation potency of CYP activities has not been previously investigated. Here, we investigated the inhibitory effects of bakuchicin on the activities of CYP isoforms by using a cocktail of probe substrates in pooled human liver microsomes (HLMs) and human recombinant cDNA-expressed CYP. Bakuchicin strongly inhibited CYP1A-mediated phenacetin O-deethylation with an IC50 value of 0.43 μM in HLMs. It was confirmed by human recombinant cDNA-expressed CYP1A1 and CYP1A2 with a Ki value of 0.11 μM and 0.32 μM, respectively. A Lineweaver-Burk plot indicated that the inhibition mechanism of bakuchicin was competitive inhibition. Overall, this is the first study to investigate the potential CYP1A1 and CYP1A2 inhibition associated with bakuchicin and to report its competitive inhibitory effects on HLMs

Association of HLA class II genes with idiopathic pulmonary arterial hypertension in Koreans

The aim of this study was to compare the frequency of the HLA-DRB1 and HLA-DQB1 alleles in Korean patients with idiopathic pulmonary arterial hypertension (IPAH) and in normal controls and to determine any association that may exist between clinical characteristics of IPAH and specific HLA alleles. IPAH patients seen between October 1998 and September 2001 were retrospectively assessed, and 19 patients and 193 controls were HLA typed at the HLA-DRB1 and DQB1 loci. Clinical characteristics and hemodynamic parameters were reviewed. The patients with IPAH had a significantly higher frequency of the HLA-DRB1*0406 allele (18% vs. 6%, p = 0.004) and the HLA-DQB1*0302 allele (24% vs. 12%, p = 0.034), as well as a significantly higher frequency of haplotype DRB1*0406-DQB1*0302 (p = 0.0006). All 6 patients with haplotype DRB1*0406-DQB1*0302 (H+ group) were women, compared with 8 of the 13 patients lacking the DRB1*0406-DQB1*0302 haplotype (H- group), but without statistical significance. Three of 19 patients showed a positive short-term hemodynamic response to NO inhalation, all 3 of whom had the DRB1*0406-DQB1*0302 haplotype. There were no other significant differences in clinical characteristics and hemodynamic parameters between the H+ and H- groups. We conclude from this study that the HLA-DRB1*0406-DQB1*0302 haplotype is associated with IPAH in Korean patients. These results suggest that certain clinical characteristics of IPAH may be controlled in part by patients' HLA alleles

Tantalum and molybdenum barriers to prevent carbon diffusion in spark plasma sintered tungsten

Carbide reduces the ductility of tungsten and leads to brittle intergranular fractures. These fractures are inevitably formed in tungsten by carbon diffusion owing to graphite mold during spark plasma sintering. Here, we introduce protective foils made up of two different carbide-forming elements, molybdenum and tantalum, to minimize the carbide formation. Cross-sectional elemental mapping shows that the tantalum foil suppresses carbon diffusion into tungsten, while the molybdenum foil is not an effective diffusion barrier. Thermodynamic-kinetic simulations demonstrate that the suppressed carbon diffusion in tantalum is attributed to high solubility and low diffusivity. Furthermore, the thermodynamically stable tantalum carbide prevents further carbon diffusion at the tantalum/tungsten interface. For the opposite reason, carbon diffuses faster not only in the molybdenum, but also at the molybdenum/tungsten interface. This study provides strategies to minimize the carbon diffusion during spark plasma sintering as well as an intuition into developing structural materials for extreme carbonaceous environments. (C) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.11Nsciescopu

Unique binding mode of Evogliptin with human dipeptidyl peptidase IV

Evogliptin ((R)-4-((R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(tert-butoxymethyl) piperazine-2-one)) is a highly potent selective inhibitor of dipeptidyl peptidase IV (DPP4) that was approved for the treatment of type 2 diabetes in South Korea. In this study, we report the crystal structures of Evogliptin, DA-12166, and DA-12228 (S,R diastereomer of Evogliptin) complexed to human DPP4. Analysis of both the structures and inhibitory activities suggests that the binding of the trifluorophenyl moiety in the S1 pocket and the piperazine-2-one moiety have hydrophobic interactions with Phe357 in the S2 extensive subsite, and that the multiple hydrogen bonds made by the (R)-β-amine group in the S2 pocket and the contacts made by the (R)-tert-butyl group with Arg125 contribute to the high potency observed for Evogliptin.11Nsciescopu

Sox7 promotes high-grade glioma by increasing VEG FR2-mediated vascular abnormality

High-grade glioma (HGG) is highly angiogenic, but antiangiogenic therapy has transient clinical benefit in only a fraction of patients. Vascular regulators of these heterogeneous responses remain undetermined. We found up-regulation of Sox7 and down-regulation of Sox17 in tumor endothelial cells (tECs) in mouse HGG. Sox7 deletion suppressed VEG FR2 expression, vascular abnormality, hypoxia-driven invasion, regulatory T cell infiltration, and tumor growth. Conversely, Sox17 deletion exacerbated these phenotypes by up-regulating Sox7 in tECs. Anti-VEG FR2 antibody treatment delayed tumor growth by normalizing Sox17-deficient abnormal vessels with high Sox7 levels but promoted it by regressing Sox7-deficient vessels, recapitulating variable therapeutic responses to antiangiogenic therapy in HGG patients. Our findings establish that Sox7 promotes tumor growth via vessel abnormalization, and its level determines the therapeutic outcome of VEG FR2 inhibition in HGG. In 189 HGG patients, Sox7 expression was heterogeneous in tumor vessels, and high Sox7 levels correlated with poor survival, early recurrence, and impaired vascular function, emphasizing the clinical relevance of Sox7 in HGG. ⓒ 2018 Kim et al