Acute toxicity of glycyrol in mice.

<p>Biochemistry in serum of mice treated with CsA or glycyrol. Dosage schedule: 500 mg/kg on day 0, 100 mg/kg on days 1 and 2; blood sampling on day 4. A: Glutamic-pyruvic transaminase; B: Glutamic-oxaloacetic transaminase; C: Total bilirubin; D: Urea nitrogen; E: Serum creatinine. Bars represent means ±SD from 7 mice. *P<0.05, **P<0.01 and ***P<0.001 for comparison with Vehicle group.</p

Effect of the peroral administration of glycyrol on immunoregulation <i>in vivo.</i>

<p>DNFB-induced DTH reaction (panel A) and carbon particle clearance test (panel B) conducted on mice given glycyrol (50 or 100 mg/kg) or CsA (50 mg/kg). The mice were initially sensitized by 50 µL of 1% DNFB on abdomens 30 min after drug administration on days 1 and 2. On day 5, 30 min after drug administration, mice were treated with 10 µL of 1% DNFB on both sides of their right ear. The mice were killed by cervical dislocation 24 h after the third sensitization. A1: ear swelling; A2: thymus; A3: spleen; B: phagocytic index. Data are shown as means ±SD from 8 mice. Differences between groups were tested by Student's t-test. # P<0.05 for comparison with Vehicle group, *P<0.05 for comparison with Model group.</p

The action of glycyrol on acute inflammation <i>in vivo.</i>

<p>Acetic acid-induced capillary permeability test. Mice were given 150 mg/kg glycyrol perorally for 5 consecutive days before the acute inflammatory test. 0.5% Evan's blue was injected into the tail vein 30 min after the last peroral administration. Permeability scored by Evans Blue concentration in peritoneal fluid (light absorbance at 590 nm). Columns represent means ±SD from 8 mice. Differences between groups were tested by Student's t-test. *P<0.05 for comparison with Model group.</p

Glycyrol inhibits transcription of NFAT and IL-2genes.

<p>RAW 264.7 cells were stimulated with PMA plus Ion or a combination of indicated concentrations glycyrol or CsA and PMA plus Ion for 24-2 gene transcription. Panel A: NFAT transcription was measured using the dual-reporter gene assay system; Panel B: IL-2 gene transcription was detected by Real-time quantitative PCR. Assays were performed in triplicate. Data represent means ± SD over three independent experiments. Statistical significance was calculated using one-way analysis of variance (ANOVA) and Bonferroni post-test. # P<0.05 for comparison with naïve group, *P<0.05 for comparison with PMA plus Ion-stimulated group.</p

Glycyrol attenuates collagen-induced arthritis.

<p>CIA was induced by intradermal injection collagen II in Freund's adjuvant as described in Materials and Methods. A – C. Glycyrol and CsA were administered perorally every day from days 21 to 42. A: Time-dependent mean clinical scores (±SD) of four paws; B: Body weight changes (mean±SD); C1: TNF-α levels in serum on day 42; C2: IL-1β levels in serum on day 42; C3: IL-17 levels in serum on day 42; C4: IL-6 in serum on day 42. Data points are means ± SD of 7 mice. Differences between groups were tested by Student's t-test. # P<0.05 for comparison with Normal group, *P<0.05 for comparison with CIA group. D. Histopathologic features of representative ankle joints of male DBA/1J mice obtained on day 42 and stained with H&E (100x original magnification). “A” represents non-immunized mice showing normal articular cartilage, absence of infiltrate in the synovium and open joint space, “B” indicates CIA mice showing marked infiltration of inflammatory cells, narrow joint space with synovial hyperplasia, and “C” and “D” represent CIA mice treated with CsA or glycyrol, respectively, showing less inflammatory cell infiltration, well-preserved joint spaces, and minimal synovial hyperplasia. “b” denotes bone tissue, whereas “c”, “s”, and “js” indicate cartilage, synovium, and joint space, respectively. E. Quantification of histological changes. Data represent means ±SD from 7 mice. *P<0.05 for comparison with CIA group.</p

Glycyrol inhibits expression of p-IκB and NF-κB.

<p>A & B: Jurkat cells were stimulated with PMA plus Ion or a combination of indicated concentrations glycyrol or CsA and PMA plus Ion for 24 h to induce IκB-α expression. A: Western blot picture of p-IκB-α; B: Quantification of Western blot. C: RAW 264.7 cells were induced with PMA plus Ion or a combination of indicated concentrations glycyrol or CsA and PMA plus Ion for 24 h to induce NF-κB expression, and measured by dual-reporter gene assay system. Assays were performed in triplicate. Data represent means ±SD over three independent experiments. # P<0.05 for comparison with naïve group, *P<0.05 for comparison with PMA plus Ion-stimulated group.</p

First-Principles Study of Lithiation of Type I Ba-Doped Silicon Clathrates

Silicon clathrate materials, previously known for their superconducting and thermoelectric characteristics, have also recently been investigated for their electrochemical properties as anodes for lithium-ion batteries due to their unique cage structure and ability to incorporate extrinsic guest atoms. To better understand the preferred structures for small degrees of lithiation, first-principles density functional theory (DFT) was used to investigate the type I clathrate compounds Si₄₆, Li_<i>x</i>Ba_<i>y</i>Si₄₆ (0 ≤ <i>x</i> ≤ 8; <i>y</i> = 6, 8), and Li_<i>x</i>Ba_<i>y</i>Al₆Si₄₀ (0 ≤ <i>x</i> ≤ 8; <i>y</i> = 6). The formation energies, electronic band structures, and density of states (DOS) were calculated. Lithium occupation in framework vacancies, empty and Ba-occupied cage cavities, and near the pentagonal and hexagonal faces of the clathrate polyhedra was considered. The data showed that Li insertion into framework or Ba vacancies could stabilize the clathrate structure. Silicon substitution by Al lowered the formation energies of the lithiated compounds and mitigated the calculated volume increase upon lithiation. The results also showed that it is energetically feasible for multiple guest atoms to be placed in the Si₂₄ cages. Changes in the clathrate atomic structure (e.g., bond lengths and angles) and electronic structure were highly dependent on the location of the Li and guest atom spacing within the clathrate framework. The results from this study can elucidate the preferred structural configurations for Li in type I, Ba-doped silicon clathrates and also be informative for efforts related to understanding the structures obtained after electrochemical insertion of lithium into silicon clathrates

DataSheet_1_Immune landscape and risk prediction based on pyroptosis-related molecular subtypes in triple-negative breast cancer.zip

The survival outcome of triple-negative breast cancer (TNBC) remains poor, with difficulties still existing in prognosis assessment and patient stratification. Pyroptosis, a newly discovered form of programmed cell death, is involved in cancer pathogenesis and progression. The role of pyroptosis in the tumor microenvironment (TME) of TNBC has not been fully elucidated. In this study, we disclosed global alterations in 58 pyroptosis-related genes at somatic mutation and transcriptional levels in TNBC samples collected from The Cancer Genome Atlas and Gene Expression Omnibus databases. Based on the expression patterns of genes related to pyroptosis, we identified two molecular subtypes that harbored different TME characteristics and survival outcomes. Then, based on differentially expressed genes between two subtypes, we established a 12-gene score with robust efficacy in predicting short- and long-term overall survival of TNBC. Patients at low risk exhibited a significantly better prognosis, more antitumor immune cell infiltration, and higher expression of immune checkpoints including PD-1, PD-L1, CTLA-4, and LAG3. The comprehensive analysis of the immune landscape in TNBC indicated that alterations in pyroptosis-related genes were closely related to the formation of the immune microenvironment and the intensity of the anticancer response. The 12-gene score provided new information on the risk stratification and immunotherapy strategy for highly heterogeneous patients with TNBC.</p

Green and Orange CdTe Quantum Dots as Effective pH-Sensitive Fluorescent Probes for Dual Simultaneous and Independent Detection of Viruses

One of the most highlighted and fastest moving interfaces of nanotechnology is the application of quantum dots (QDs) in biology. The unparalleled advantages of the size-tunable fluorescent emission and the simultaneous excitation at a single wavelength make QDs the great possibility for use in optical encoding detection. In this paper, we report that green and orange CdTe QDs as convenient, cheap, reversible, and effective pH-sensitive fluorescent probes could monitor the proton (H+) flux driven by ATP synthesis for dual simultaneous and independent detection of viruses on the basis of antibody−antigen reactions. A new kind of biosensor (consisting of the mixture of green-QDs-labeled chromatophores and orange-QDs-labeled chromatophores) fluorescent measurement system was established for rapid, simultaneous, and independent detection of two different kinds of viruses (i.e., H9 avian influenza virus and MHV68 virus). It is crucial to find that the green and orange QDs labeled biosensors coexisting in the detection system can work independently and do not interfere with each another in the fluorescence assays. In addition, a primary steady electric double layer (EDL) model for the QDs biosensors was proposed to illustrate the mechanism of simultaneous and independent detection of the biosensors. We believe that the pH-sensitive CdTe QDs based detection system, described in this paper, is an important step toward optical encoding and has a great potential for simultaneous and independent qualitative and quantitative multiple detection systems

Table_1_An Inhibitor of Grp94 Inhibits OxLDL-Induced Autophagy and Apoptosis in VECs and Stabilized Atherosclerotic Plaques.XLSX

Background: Oxidized low-density lipoprotein (oxLDL) induces vascular endothelial cell (VEC) injury and atherosclerosis through activating endoplasmic reticulum stress. Expression of glucose-regulated protein 94 (Grp94) is induced by endoplasmic reticulum stress and Grp94 is involved in cardiovascular diseases. This study aimed to determine the role of Grp94 in oxLDL-induced vascular endothelial cell injury and atherosclerosis.Methods and Results: An inhibitor of Grp94, HCP1, was used to investigate the role of Grp94 in oxLDL-induced VEC injury in human umbilical vein endothelial cells and atherosclerosis in apolipoprotein E−/− mice. Results showed that HCP1 inhibited autophagy and apoptosis induced by oxLDL in VECs. And we found that Grp94 might interact with adenosine monophosphate-activated protein kinase (AMPK) and activate its activity. HCP1 inhibited AMPK activity and overexpression of Grp94 blocked the effect of HCP1. Besides, HCP1 activated the activity of mechanistic target of rapamycin complex 1 (mTORC1), co-treatment with AMPK activator acadesine eliminated the effect of HCP1 on mTORC1 activity as well as autophagy. In apolipoprotein E−/− mice, HCP1 suppressed autophagy and apoptosis of atherosclerotic plaque endothelium. In addition, HCP1 increased the content of collagen, smooth muscle cells, and anti-inflammatory macrophages while reducing the activity of MMP-2/9 and pro-inflammatory macrophages in the atherosclerotic lesion.Conclusion: HCP1 inhibited oxLDL-induced VEC injury and promoted the stabilization of atherosclerotic plaque in apoE−/− mice. Grp94 might be a potential therapeutic target in the clinical treatment of atherosclerosis.</p