To discover small-molecule cancer immunotherapy candidates through targeting Indoleamine 2,3-dioxygenase 1 (IDO1), twenty–five new berberine (BBR) derivatives defined with substituents on position 3 ...or 9 were synthesized and examined for repression of IFN-γ-induced IDO1 promoter activities. Structure–activity relationship (SAR) indicated that large volume groups at the 9-position might be beneficial for potency. Among them, compounds 2f, 2i, 2n, 2o and 8b exhibited increased activities, with inhibition rate of 71–90% compared with BBR. Their effects on IDO1 expression were further confirmed by protein level as well. Furthermore, compounds 2i and 2n exhibited anticancer activity by enhancing the specific lysis of NK cells to A549 through IDO1, but not cytotoxicity. Preliminary mechanism revealed that both of them inhibited IFN-γ-induced IDO1 expression through activating AMPK and subsequent inhibition of STAT1 phosphorylation. Therefore, compounds 2i and 2n have been selected as IDO1 modulators for small-molecule cancer immunotherapy for next investigation.
Compounds 2i and 2n are considered to be the promising IDO modulators for small-molecule cancer immunotherapy for next investigation. Display omitted
•New BBR analogues were synthesized and evaluated for the IDO1 expression activity.•Compounds 2i and 2n greatly reduced IDO1 expression as well as on protein level.•Both of them showed good anticancer activity in vitro, but not via cytotoxicity.•Both of them are the potential IDO modulators for cancer immunotherapy.
The Selective Laser Melting (SLM) fabrication process is complex and it is crucial to understand the phenomena that will occur to better control it. In this paper, an FE model on SLM that considers ...powder-to-solid transition together with an effective method to achieve volume shrinkage and material removal has been created. Experiments were conducted to validate the model. A detailed discussion on the progression of the melt pool and the rate of temperature change has been made. Parametric study with the laser power and scan speed as variables has been conducted to identify their relationships with the melt dimensions, melting and evaporation of powder and rates of temperature change.
Nineteen new quinoline derivatives were prepared via the Mannich reaction and evaluated for their antibacterial activities against both Gram-positive (G⁺) and Gram-negative (G
) bacteria, taking ...compound
as the lead. Among the target compounds, quinolone coupled hybrid
exerted the potential effect against most of the tested G⁺ and G
strains with MIC values of 0.125⁻8 μg/mL, much better than those of
. Molecular-docking assay showed that compound
might target both bacterial LptA and Top IV proteins, thereby displaying a broad-spectrum antibacterial effect. This hybridization strategy was an efficient way to promote the antibacterial activity of this kind, and compound
was selected for the further investigation, with an advantage of a dual-target mechanism of action.
Ambient air pollution is a major global health concern. Yet, no study has thoroughly assessed its link to respiratory mortality. Our research evaluated the combined and individual effects of air ...pollutants on respiratory mortality risks based on the UK Biobank. A total of 366,478 participants were studied. A Cox proportional hazards model was used to estimate the respiratory mortality risk from combined long-term exposure to five pollutants, summarized as a weighted air pollution score. During a median of 13.6 years of follow-up, 6113 deaths due to respiratory diseases were recorded. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) of respiratory diseases were 2.64 (2.05–3.39), 1.62 (1.23–2.12), 2.06 (1.73–2.45), 1.20 (1.16–1.25), and 1.07 (1.05–1.08) per 10 μg/m3 increase in PM2.5, PM2.5–10, PM10, NO2, and NOx, respectively. The air pollution score showed a dose-response association with an elevated respiratory mortality risk. The highest versus lowest quartile air pollution score was linked to a 44% increase in respiratory mortality risk (HR 1.44, 95% CI: 1.33–1.57), with consistent findings in subgroup and sensitivity analyses. Long-term individual and joint air-pollutant exposure showed a dose-response association with an increased respiratory mortality risk, highlighting the importance of a comprehensive air-pollutant assessment to protect public health.
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•Air pollution is a risk factor for respiratory mortality.•Long-term exposure to air pollution increased respiratory mortality risk.•The AP score showed a dose-response association with respiratory mortality risk.
A series of new 13-substituted cycloberberine (CBBR) derivatives were prepared and evaluated for their antibacterial activities against Gram-positive bacteria taking CBBR as the lead. ...Structure-activity relationship revealed that the introduction of a suitable electron-donating group at the 13-position in CBBR might be beneficial for the antibacterial potency. Among them, compounds 5b and 5w exhibited high potency against methicillin-sensitive (MSSA) and resistant strains of S. aureus (MRSA) with MIC values of 1–4 μg/mL. Both of them also displayed high stabilities in blood, and good in vivo safety profiles with LD50 values of 65.6 and 41.2 mg kg−1 in intravenous route respectively. Molecular docking analysis indicated that compound 5b might target FtsZ protein that could inhibit cell division, with the advantage of activity against multidrug resistant S. aureus. Therefore, we consider 13-substituted CBBR derivatives to be a novel class of anti-MRSA agents worthy of further investigation.
Compounds 5b and 5w are considered to be promising antimicrobial agents against MSSA and MRSA strains. Display omitted
•13-substituted CBBR analogues were identified as promising antimicrobial agents.•Compounds 5b and 5w exhibited excellent activities against MRSA strains.•Both of them displayed high stabilities and good in vivo safety profiles.•5b might act upon bacteria through inhibiting FtsZ protein of S. aureus.
Biofouling and corrosion, caused by marine organisms, pose significant challenges in the marine industry. Fe-based amorphous coatings have demonstrated remarkable corrosion resistance and hold ...promise for marine applications. However, they lack sufficient antifouling properties. Herein, we present a novel approach to enhance the antifouling properties of Fe-based amorphous coatings through co-modification with polydimethylsiloxane (PDMS) and cuprous oxide (Cu2O). The PDMS/Cu2O antifouling layer was successfully applied to the Fe-based amorphous coating with the bonding strength exceeding 2 MPa. The PDMS/Cu2O- anchored Fe-based amorphous coating (designated as PCA coating) demonstrates outstanding antifouling performance, showcasing 83.9 % resistance to protein, 99 % resistance to algae, high resistance to bacteria and mussel adhesion, and successful antifouling performance in practical marine field tests. The remarkable antifouling properties of the PCA coating stem from its dual capacity of killing and resisting to deter organism attachment across different length scales. And the enhanced anti-corrosion performance of the PCA coating was verified through electrochemical impedance spectra (EIS). This study presents an innovative approach to designing marine coatings with anti-fouling and anti-corrosion capabilities.
•PDMS/Cu2O-anchored amorphous coatings with integrated antifouling and anticorrosion functionality are designed•The coating exhibits 83.9 % resistance to protein, 99 % resistance to algae, high resistance to mussel adhesion•The coating exhibits good antifouling performance in practical marine field tests•The remarkable antifouling properties stem from dual capacity of killing and resisting to deter organism attachment
This study was designed to improve the absorption and hypoglycemic efficacy of berberine (BBR), which is a substrate of P-glycoprotein (P-gp), by combination with a P-gp inhibitor tetrandrine (Tet). ...Flow cytometry and LC-MS/MS were used to determine the cellular efflux or retention of chemicals. Pharmacokinetic study was performed in ICR mice following oral administration of the study compounds. The hypoglycemic efficacies of the compounds were evaluated in diabetic KK-Ay mice. In the in vitro experiments, Tet significantly inhibited the efflux and increased the uptake of P-gp substrates rhodamine-123 as well as BBR in MCF7/DOX cells and Caco-2 intestinal cells. Meanwhile, Tet greatly reduced the expression of P-gp in Caco-2 cells. The inhibition of BBR efflux by Tet was translated into improved pharmacokinetics in vivo. When co-administered, Tet dose-dependently increased the average maximum concentration (Cmax) and area under concentration–time curve (AUC0–24) of BBR in mice. Tet itself had no impact on glucose metabolism. However, it greatly potentiated the hypoglycemic efficacy of BBR in diabetic KK-Ay mice. In addition, we found that Tet had moderate inhibitory effect on the catalytic activity of CYP3A4, which played a role in the bio-transformation of BBR, and this may also take part in the improvement of the pharmacokinetics of BBR. In summary, combination with P-gp inhibitors such as Tet can improve the pharmacokinetics and hypoglycemic efficacy of BBR greatly; this implicates a feasible strategy for exploring the therapeutic effects of BBR and other pharmaceuticals which are substrates of P-gp.
Biofouling and corrosion of underwater equipment induced by marine organisms have become major issues in the marine industry. The superior corrosion resistance of Fe-based amorphous coatings makes ...them suitable for marine applications; however, they have a poor antifouling ability. In this work, a hydrogel-anchored amorphous (HAM) coating with satisfactory antifouling and anticorrosion performance is designed, utilizing an interfacial engineering strategy involving micropatterning, surface hydroxylation, and a dopamine intermediate layer to increase the adhesion strength between the hydrogel layer and the amorphous coating. The as-obtained HAM coating exhibits exceptional antifouling properties, achieving 99.8% resistance to algae, 100% resistance to mussels, and excellent biocorrosion resistance against Pseudomonas aeruginosa. Antifouling and anticorrosion performance of the HAM coating was also explored by conducting a marine field test in the East China Sea, and no signs of corrosion and fouling are observed after 1 month of immersion. It is revealed that the outstanding antifouling properties stem from the killing–resisting–camouflaging trinity that resists organism attachment across different length scales, and the excellent anticorrosion performance originates from the remarkable barrier of the amorphous coating against Cl– ion diffusion and microbe-induced biocorrosion. This work presents a novel methodology for designing marine protective coating with excellent antifouling and anticorrosion properties.
Preventing filoviruses in the entry stage is an attractive antiviral strategy. Taking aloperine, a Chinese natural herb with an endocyclic skeleton, as the lead, 23 new aloperine derivatives were ...synthesized and evaluated for their anti-filovirus activities including ebola virus (EBOV) and marburg virus (MARV) using pseudotyped virus model. Structure-activity relationship (SAR) analysis indicated that the introduction of a 12N-dichlorobenzyl group was beneficial for the potency. Compound 2e exhibited the most potent anti-EBOV and anti-MARV effects both in vitro and in vivo. It also displayed a good pharmacokinetic and safety profile in vivo, indicating an ideal druglike feature. The primary mechanism study showed that 2e could block a late stage of viral entry, mainly through inhibiting cysteine cathepsin B activity of host components. We consider compound 2e to be a promising broad-spectrum anti-filovirus agent with the advantages of a unique chemical scaffold and a specific biological mechanism.
Aloperine derivative 2e was identified to exert a broad-spectrum anti-filovirus activity mainly through targeting a host protein cysteine cathepsin B to block a late stage of viral entry. Display omitted
•23 new aloperines were synthesized and evaluated for the anti-EBOV activity.•Compound 2e exhibited potent anti-EBOV/MARV effects both in vitro and in vivo.•Compound 2e displayed a good pharmacokinetic and safety profile in vivo.•Compound 2e could inhibit cat B activity to block the late stage of viral entry.
Stimulator of interferon genes (STING) activation favors effective innate immune responses against viral infections. Its role in chronic rhinosinusitis with nasal polyps (CRSwNP) remains unknown.
Our ...aim was to explore the expression, regulation, and function of STING in CRSwNP.
STING expression in sinonasal mucosal samples was analyzed by means of quantitative RT-PCR, immunohistochemistry, flow cytometry, and Western blotting. Regulation and function of STING expression were explored by using cultured primary human nasal epithelial cells (HNECs) and cells of the line BEAS-2B in vitro.
STING expression was reduced in eosinophilic nasal polyps compared with that in noneosinophilic nasal polyps and control tissues. STING was predominantly expressed by epithelial cells in nasal tissue and was downregulated by IL-4 and IL-13 in a signal transducer and activator of transcription 6 (STAT6)-dependent manner. HNECs derived from eosinophilic polyps displayed compromised STING-dependent type I interferon production but heightened IL-13–induced STAT6 activation and CCL26 production as compared with HNECs from noneosinophilic polyps and control tissues, which were rescued by exogenous STING overexpression. Knocking down or overexpressing STING decreased or enhanced expression of suppressor of cytokine signaling 1 (SOCS1) in BEAS-2B cells, respectively, independent of the canonic STING pathway elements TBK1 and IRF3. Knocking down SOCS1 abolished the inhibitory effect of STING on IL-13 signaling in BEAS-2B cells. STING expression was positively correlated with SOCS1 expression but negatively correlated with CCL26 expression in nasal epithelial cells from patients with CRSwNP.
Reduced STING expression caused by the type 2 milieu not only impairs STING-dependent type I interferon production but also amplifies IL-13 signaling by decreasing SOCS1 expression in nasal epithelial cells in eosinophilic CRSwNP.
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