Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignant tumor whose effective treatment has not been found. The redox state and proliferative activity of PDAC cells are maintained by the ...conversion of aspartic acid in the cytoplasm into oxaloacetate though aspartate aminotransferase 1 (GOT1). Therefore, GOT1 inhibitors as a potential approach for treating PDAC have attracted more attention of researchers. Ziprasidone effectively inhibited GOT1 in a non-competitive manner
.
The potential cytotoxicity and anti-proliferation effects of ziprasidone against PDAC cells in vitro and in vivo were evaluated. Ziprasidone can induce glutamine metabolism disorder and redox state imbalance of PDAC cells by targeting GOT1, thereby inhibiting proliferation, preventing migration, and inducing apoptosis. Ziprasidone displayed significant in vivo antitumor efficacy in SW1990 cell-derived xenografts. What’s more, knockdown of GOT1 in SW1990 reduced the anti-proliferative effects of ziprasidone. As a novel GOT1 inhibitor, ziprasidone may be a lead compound for the treatment of PDAC.
Key messages
Small molecule inhibitors targeting GOT1 may provide a therapeutic target in PDAC.
Ziprasidone effectively inhibited GOT1 enzyme in a non-competitive manner.
Ziprasidone repressed glutamine metabolism and inhibited the growth of tumor in vivo.
Knockdown of GOT1 decreased the anti-proliferative effects of ziprasidone.
Graphic abstract
The purpose of this work is to study the effect of anisotropic plasticity on the micro-deep drawing of the 304 stainless steel foils through a combination of experimental testing and numerical ...modeling. A phenomenological anisotropic model, with the Yld2004-18p yield function, is used to model the anisotropic plasticity deformation of the material. Based on the miniature tensile experimental data and Voce's hardening law, the coefficients in the Yld2004-18p function were calibrated. The FE modelling was implemented using ABAQUS to simulate the micro-deep drawing experiments. The wall thickness and height of the cylindrical cup obtained by the simulation have shown to be reasonably close to the experimental values, and the distribution of ears is the same as the experimental results. It has shown that the Yld2004-18p anisotropic yield function can accurately describe the anisotropic behavior of 304 stainless steel foils during the micro-deep drawing process.
Ratiometric electrochemiluminescence (ECL) sensors can efficiently remove environmental interference to attain precise detection. Nonetheless, two eligible luminophores or coreactants were usually ...needed, increasing the complexity and restricting their practical application. In this study, a single luminophore of luminol with a single coreactant of H2O2 was employed to construct a dual-potential ratiometric ECL sensor for the detection of carcinoembryonic antigen (CEA). The produced palladium nanoclusters (Pd NCs) employing a DNA duplex as a template could not only stimulate luminol to produce cathodic ECL (I cathodic) but also quench its anodic ECL (I anodic). During the detection process, CEA could damage the double-stranded structure and reduce the Pd NCs’ amount, triggering a significant decrease in the ratio of I cathodic to I anodic (I cathodic /I anodic) and thereby achieving sensitive CEA’s detection. Furthermore, the I cathodic /I anodic was independent of the H2O2 concentration, which avoided a prejudicial effect from H2O2 decomposition and considerably enhanced the detection’s reliability. The developed ratiometric ECL sensor demonstrated a sensitive detection toward CEA with a wide linear range from 100 ag/mL to 10 ng/mL and a detection limit of 87.1 ag/mL (S/N = 3). In conclusion, this study offers a new idea for constructing ratiometric ECL sensors based on a single luminophore and technical support for cancer’s early diagnosis.
Along with functionally intact insulin, diabetes-associated insulin peptides are secreted by β cells. By screening the expression and functional characterization of olfactory receptors (ORs) in ...pancreatic islets, we identified Olfr109 as the receptor that detects insulin peptides. The engagement of one insulin peptide, insB:9-23, with Olfr109 diminished insulin secretion through Gi-cAMP signaling and promoted islet-resident macrophage proliferation through a β cell-macrophage circuit and a β-arrestin-1-mediated CCL2 pathway, as evidenced by β-arrestin-1
mouse models. Systemic Olfr109 deficiency or deficiency induced by Pdx1-Cre
Olfr109
specifically alleviated intra-islet inflammatory responses and improved glucose homeostasis in Akita- and high-fat diet (HFD)-fed mice. We further determined the binding mode between insB:9-23 and Olfr109. A pepducin-based Olfr109 antagonist improved glucose homeostasis in diabetic and obese mouse models. Collectively, we found that pancreatic β cells use Olfr109 to autonomously detect self-secreted insulin peptides, and this detection arrests insulin secretion and crosstalks with macrophages to increase intra-islet inflammation.
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Cytarabine has a poor oral absorption due to its rapid deamination and poor membrane permeability. Bile acid transporters are highly expressed both in enterocytes and hepatocytes and ...to increase the oral bioavailability and investigate the potential application of cytarabine for liver cancers, a transporter- recognizing prodrug strategy was applied to design and synthesize four conjugates of cytarabine with cholic acid (CA), chenodeoxycholic acid (CDCA), hyodeoxycholic acid (HDCA) and ursodeoxycholic acid (UDCA). The anticancer activities against HepG2 cells were evaluated by MTT assay and the role of bile acid transporters during cellular transport was investigated in a competitive inhibition experiment. The in vitro and in vivo metabolic stabilities of these conjugates were studied in rat plasma and liver homogenates. Finally, an oral bioavailability study was conducted in rats. All the cholic acid-cytarabine conjugates (40μM) showed potent antiproliferative activities (up to 70%) against HepG2 cells after incubation for 48h. The addition of bile acids could markedly reduce the antitumor activities of these conjugates. The N4-ursodeoxycholic acid conjugate of cytarabine (compound 5) exhibited optimal stability (t1/2=90min) in vitro and a 3.9-fold prolonged half-life of cytarabine in vivo. More importantly, compound 5 increased the oral bioavailability 2-fold compared with cytarabine. The results of the present study suggest that the prodrug strategy based on the bile acid transporters is suitable for improving the oral absorption and the clinical application of cytarabine.
The protein-coding exome of a patient with a monogenic disease contains about 20,000 variants, only one or two of which are disease causing. We found that 58% of rare variants in the protein-coding ...exome of the general population are located in only 2% of the genes. Prompted by this observation, we aimed to develop a gene-level approach for predicting whether a given human protein-coding gene is likely to harbor disease-causing mutations. To this end, we derived the gene damage index (GDI): a genome-wide, gene-level metric of the mutational damage that has accumulated in the general population. We found that the GDI was correlated with selective evolutionary pressure, protein complexity, coding sequence length, and the number of paralogs. We compared GDI with the leading gene-level approaches, genic intolerance, and de novo excess, and demonstrated that GDI performed best for the detection of false positives (i.e., removing exome variants in genes irrelevant to disease), whereas genic intolerance and de novo excess performed better for the detection of true positives (i.e., assessing de novo mutations in genes likely to be disease causing). The GDI server, data, and software are freely available to noncommercial users from lab.rockefeller.edu/casanova/GDI.
This study aimed to develop a quenching-type electrochemiluminescence (ECL) immunosensor for human epidermal growth factor receptor (Her-2) detection. Firstly, Pd/NiFeOx nanoflowers decorated by in ...situ formation of gold nanoparticles (Au NPs) and 2D Ti
3
C
2
MXene nanosheets were synthesized (AuPd/NiFeOx/Ti
3
C
2
) as carriers to load luminol and primary antibodies. Impressively, AuPd/NiFeOx/Ti
3
C
2
with excellent peroxidase-like activity could accelerate the decomposition of the coreactant H
2
O
2
generating more reactive oxygen species (ROSs) under the working potential from 0 to 0.8 V, resulting in highly efficient ECL emission at 435-nm wavelengths. The introduction of tungsten-based polyoxometalate nanoclusters (W-POM NCs) which exhibit remarkable ROSs-scavenging activity as secondary antibody labels could improve the sensitivity of immunosensors. The ZnO nanoflowers were employed to encapsulate minute-sized W-POM NCs, and polydopamine was self-polymerized on the surface of Zn(W-POM)O to anchor secondary antibodies. The mechanism of the quenching strategy was explored and it was found that W-POM NCs could consume ROSs by the redox reaction of W
5+
resulting in W
6+
. The proposed ECL immunosensor displayed a wide linear response range of 0.1 pg·mL
−1
to 50 ng·mL
−1
, and a low detection limit of 0.036 pg mL
−1
(S/N = 3). The recoveries ranged from 93.9 to 99.4%, and the relative standard deviation (RSD) was lower than 10%. This finding is promising for the design of detecting new protein biomarkers.
Graphical abstract
Inflammatory bowel disease (IBD) is characterized by chronic and relapsing intestinal inflammation, which currently lacks safe and effective medicine. Some previous studies indicated that ...Astragaloside IV (AS-IV), a natural saponin extracted from the traditional Chinese medicine herb
, alleviates the experimental colitis symptoms
and
. However, the mechanism of AS-IV on IBD remains unclear. Accumulating evidence suggests that M2-polarized intestinal macrophages play a pivotal role in IBD progression. Here, we found that AS-IV attenuated clinical activity of DSS-induced colitis that mimics human IBD and resulted in the phenotypic transition of macrophages from immature pro-inflammatory macrophages to mature pro-resolving macrophages.
, the phenotype changes of macrophages were observed by qRT-PCR after bone marrow-derived macrophages (BMDMs) were induced to M1/M2 and incubated with AS-IV, respectively. In addition, AS-IV was effective in inhibiting pro-inflammatory macrophages and promoting the pro-resolving macrophages to ameliorate experimental colitis
the regulation of the STAT signaling pathway. Hence, we propose that AS-IV can ameliorate experimental colitis partially by modulating macrophage phenotype by remodeling the STAT signaling, which seems to have an essential function in the ability of AS-IV to alleviate the pathological progress of IBD.
For aerospace applications, honeycomb sandwich panels may have small perforations on the cell walls of the honeycomb core to equilibrate the internal core pressure with external gas pressure, which ...prevent face-sheet/core debonding due to pressure build-up at high temperature. We propose a new form of perforation on the cell walls of honeycomb sandwich panels to reduce the influence of the perforations on the cell walls on the mechanical properties. In this paper, the high temperature mechanical properties of a new vented Ti-6Al-4V honeycomb sandwich panel were investigated. A vented Ti-6AL-4V honeycomb sandwich panel with 35Ti-35Zr-15Cu-15Ni as the filler alloy was manufactured by high-temperature brazing. The element distribution of the brazed joints was examined by means of SEM (scanning electron microscopy) and EDS (energy-dispersive spectroscopy) analyses. Compared to the interaction between the face-sheets and the brazing filler, the diffusion and reaction between the honeycomb core and the brazing filler were stronger. The flatwise compression and flexural mechanical properties of the vented honeycomb sandwich panels were investigated at 20, 160, 300, and 440 °C, respectively. The flatwise compression strength, elastic modulus, and the flexural strength of the vented honeycomb sandwich panels decreased with the increase of temperature. Moreover, the flexural strength of the L-direction sandwich panels was larger than that of the W-direction sandwich panels at the same temperature. More importantly, the vented honeycomb sandwich panels exhibited good compression performance similar to the unvented honeycomb sandwich panels, and the open holes on the cell walls have no negative effect on the compression performance of the honeycomb sandwich panels in these conditions. The damage morphology observed by SEM revealed that the face-sheets and the brazing zone show ductile and brittle fracture behaviors, respectively.
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