Metabolism and Metabolic Inhibition of Xanthotoxol in Human Liver Microsomes

Cytochrome p450 (CYP450) enzymes are predominantly involved in Phase I metabolism of xenobiotics. In this study, the CYP450 isoforms involved in xanthotoxol metabolism were identified using recombinant CYP450s. In addition, the inhibitory effects of xanthotoxol on eight CYP450 isoforms and its pharmacokinetic parameters were determined using human liver microsomes. CYP1A2, one of CYP450s, played a key role in the metabolism of xanthotoxol compared to other CYP450s. Xanthotoxol showed stronger inhibition on CYP3A4 and CYP1A2 compared to other isoenzymes with the IC50 of 7.43 μM for CYP3A4 and 27.82 μM for CYP1A2. The values of inhibition kinetic parameters (Ki) were 21.15 μM and 2.22 μM for CYP1A2 and CYP3A4, respectively. The metabolism of xanthotoxol obeyed the typical monophasic Michaelis-Menten kinetics and Vmax, Km, and CLint values were calculated as 0.55 nmol·min−1·mg−1, 8.46 μM, and 0.06 mL·min−1·mg−1. In addition, the results of molecular docking showed that xanthotoxol was bound to CYP1A2 with hydrophobic and π-π bond and CYP3A4 with hydrogen and hydrophobic bond. We predicted the hepatic clearance (CLh) and the CLh value was 15.91 mL·min−1·kg−1 body weight. These data were significant for the application of xanthotoxol and xanthotoxol-containing herbs

The tonoplast-localized transporter OsHMA3 plays an important role in maintaining Zn homeostasis in rice

In order to respond to fluctuating zinc (Zn) in the environment, plants must have a system to control Zn homeostasis. However, how plants maintain an appropriate level of Zn during their growth and development is still poorly understood. In this study, we found that OsHMA3, a tonoplast-localized transporter for Zn/Cd, plays an important role in Zn homeostasis in rice. Accessions with the functional allele of OsHMA3 showed greater tolerance to high Zn than those with the non-functional allele based on root elongation test. A 67Zn-labeling experiment showed that accessions with loss of function of OsHMA3 had lower Zn accumulation in the roots but similar concentrations in the shoots compared with functional OsHMA3 accessions. When exposed to Zn-free growing medium, the concentration in the root cell sap was rapidly decreased in accessions with functional OsHMA3, but less dramatic changes were observed in non-functional accessions. A mobility experiment showed that more Zn in the roots was translocated to the shoots in accessions with functional OsHMA3. Higher expression levels of OsZIP4, OsZIP5, OsZIP8, and OsZIP10 were found in the roots of accessions with functional OsHMA3 in response to Zn deficiency. Taken together, our results indicate that OsHMA3 plays an important role in rice roots in both Zn detoxification and storage by sequestration into the vacuoles, depending on Zn concentration in the environment

Supersymmetric Extension of the Minimal Dark Matter Model

The minimal dark matter model is given a supersymmetric extension. A super SU(2)L quintuplet is introduced with its fermionic neutral component still being the dark matter, the dark matter particle mass is about 19.7 GeV. Mass splitting among the quintplet due to supersymmetry particles is found to be negligibly small compared to the electroweak corrections. Other properties of this supersymmetry model are studied, it has the solutions to the PAMELA and Fermi-LAT anomaly, the predictions in higher energies need further experimental data to verify.Comment: 14 pages, 7 figures, accepted for publication in Chinese Physics C, typos correcte

The treatment of a Morel-Lavallée lesion of the thigh with incision and drainage along with tissue debridement and a surgically placed drain: A case report and literature review

BackgroundA Morel-Lavallée lesion (MLL) is a rare closed degloving injury that usually occurs around the hips and is associated with pelvic fractures after high-energy trauma, which is commonly overshadowed by other severe post-traumatic manifestations. An isolated MLL, mostly caused by low-energy violence, is even rarer. Thus, the rates of misdiagnosis and missed diagnosis are often high. In this case report and literature review, we review the pathophysiology, clinical manifestations, imaging data, and treatment of this lesion to increase awareness of this rare disease.Case reportWe report the case of an isolated MLL in the right thigh caused by trauma, which happened to be one of missed diagnosis both at the initial visit and at the return visit of the patient, with a significant sign of a mass on MRI. Given the size of the lesion, open debridement and irrigation were adopted to treat the lesion, and the patient recovered well post-operatively.ConclusionYoung surgeons should pay attention to the MLL with sufficient recognization to avoid missed diagnosis and misdiagnosis. Comprehensive physical examination and imaging data play important roles in the diagnosis of MLL. In the early stages of this injury, a detailed history review combined with physical examination and MRI, can reduce the rates of missed diagnosis and misdiagnosis. The choice of the therapeutic scheme depends on the size and severity of the lesion. For an isolated MLL, compared with conservative treatments, we suggest that incision and drainage, along with tissue debridement and a surgically placed drain, will reduce the rates of infection and recurrence

Dark Energy Perturbations Revisited

In this paper we study the evolution of cosmological perturbations in the presence of dynamical dark energy, and revisit the issue of dark energy perturbations. For a generally parameterized equation of state (EoS) such as w_D(z) = w_0+w_1\frac{z}{1+z}, (for a single fluid or a single scalar field ) the dark energy perturbation diverges when its EoS crosses the cosmological constant boundary w_D=-1. In this paper we present a method of treating the dark energy perturbations during the crossing of the $w_D=-1$ surface by imposing matching conditions which require the induced 3-metric on the hypersurface of w_D=-1 and its extrinsic curvature to be continuous. These matching conditions have been used widely in the literature to study perturbations in various models of early universe physics, such as Inflation, the Pre-Big-Bang and Ekpyrotic scenarios, and bouncing cosmologies. In all of these cases the EoS undergoes a sudden change. Through a detailed analysis of the matching conditions, we show that \delta_D and \theta_D are continuous on the matching hypersurface. This justifies the method used[1-4] in the numerical calculation and data fitting for the determination of cosmological parameters. We discuss the conditions under which our analysis is applicable.Comment: 10 pages and 1 figure

A Novel Immune Classification for Predicting Immunotherapy Responsiveness in Patients With Adamantinomatous Craniopharyngioma

Adamantinomatous craniopharyngioma (ACP) is the most common tumor of the sellar region in children. The aggressive behavior of ACP challenges the treatment for it. However, immunotherapy is rarely studied in ACP. In this research, we performed unsupervised cluster analysis on the 725 immune-related genes and arrays of 39 patients with ACP patients in GSE60815 and GSE94349 databases. Two novel immune subtypes were identified, namely immune resistance (IR) subtype and immunogenic (IG) subtype. Interestingly, we found that the ACPs with IG subtype (34.78%, 8/23) were more likely to respond to immunotherapy than the ACPs with IR subtype (6.25%, 1/16) via tumor immune dysfunction and exclusion (TIDE) method. Simultaneously, the enrichment analysis indicated that the differentially expressed genes (DEGs) (p < 0.01, FDR < 0.01) of the IG subtype were chiefly involved in inflammatory and immune responses. However, the DEGs of the IR subtype were mainly involved in RNA processing. Next, immune infiltration analysis revealed a higher proportion of M2 macrophage in the IG subtype than that in the IR subtype. Compared with the IR subtype, the expression levels of immune checkpoint molecules (PD1, PDL1, PDL2, TIM3, CTLA4, Galectin9, LAG3, and CD86) were significantly upregulated in the IG subtype. The ssGSEA results demonstrated that the biofunction of carcinogenesis in the IG subtype was significantly enriched, such as lymphocyte infiltration, mesenchymal phenotype, stemness maintenance, and tumorigenic cytokines, compared with the IR subtype. Finally, a WDR89 (the DEG between IG and IR subtype)-based nomogram model was constructed to predict the immune classification of ACPs with excellent performance. This predictive model provided a reliable classification assessment tool for clinicians and aids treatment decision-making in the clinic