A series of 2‐cyclopropyl‐5‐(5‐(6‐methylpyridin‐2‐yl)‐2‐substituted‐1H‐imidazol‐4‐yl)‐6‐phenylimidazo2,1‐b1,3,4thiadiazoles (15a–t and 16a–f) were synthesized and their antibacterial activities were ...evaluated. More than half of the compounds showed moderate or strong antibacterial activity. Among them, compounds 15t (MIC=1–2 μg/mL) and 16d (MIC=0.5 μg/mL) showed the strongest antibacterial activities. Notably, compound 16d did not exhibit cytotoxicity in HepG2 cells and did not show hemolysis like the positive control compound Gatifloxacin. The results suggest that compound 16d should be further investigated as a candidate antibacterial agent.
Neurofibrillary tangles of hyperphosphorylated tau protein (p-tau) are a key pathological feature of Alzheimer's disease (AD). Tau phosphorylation is suggested to be secondary to amyloid-beta (Aβ) ...accumulation. However, the mechanism by which Aβ induces tau phosphorylation in neurons remains unclear. Neurotrophin receptor p75 (p75NTR) is a receptor for Aβ and mediates Aβ neurotoxicity, implying that p75NTR may mediate Aβ-induced tau phosphorylation in AD. Here, we showed that Aβ-induced tau hyperphosphorylation and neurodegeneration, including tau phosphorylation, synaptic disorder and neuronal loss, in the brains of both male wild-type (Wt) mice and male P301L transgenic mice (a mouse model of human tauopathy) were alleviated by genetic knockout of p75NTR in the both mouse models. We further confirmed that the activation or inhibition of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase-3β (GSK3β) significantly changed Aβ/p75NTR-mediated p-tau levels in neurons. Treatment of male P301L mice with soluble p75NTR extracellular domain (p75ECD-Fc), which antagonizes the binding of Aβ to p75NTR, suppressed tau hyperphosphorylation. Taken together, our findings suggest that p75NTR meditates Aβ-induced tau pathology and is a potential druggable target for AD and other tauopathies.
•p75NTR mediates Aβ-induced neuronal tau hyperphosphorylation.•The calpain/CDK5 and AKT/GSK3β pathways are involved in Aβ/p75NTR-induced tau hyperphosphorylation.•Modulation of p75NTR is a potential therapeutic approach to rescue brain tau pathology in AD.
Cerebral amyloid-β (Aβ) accumulation due to impaired Aβ clearance is a pivotal event in the pathogenesis of Alzheimer’s disease (AD). Considerable brain-derived Aβ is cleared via transporting to the ...periphery. The liver is the largest organ responsible for the clearance of metabolites in the periphery. Whether the liver physiologically clears circulating Aβ and its therapeutic potential for AD remains unclear. Here, we found that about 13.9% of Aβ42 and 8.9% of Aβ40 were removed from the blood when flowing through the liver, and this capacity was decreased with Aβ receptor LRP-1 expression down-regulated in hepatocytes in the aged animals. Partial blockage of hepatic blood flow increased Aβ levels in both blood and brain interstitial fluid. The chronic decline in hepatic Aβ clearance via LRP-1 knockdown specific in hepatocytes aggravated cerebral Aβ burden and cognitive deficits, while enhancing hepatic Aβ clearance via LRP-1 overexpression attenuated cerebral Aβ deposition and cognitive impairments in APP/PS1 mice. Our findings demonstrate that the liver physiologically clears blood Aβ and regulates brain Aβ levels, suggesting that a decline of hepatic Aβ clearance during aging could be involved in AD development, and hepatic Aβ clearance is a novel therapeutic approach for AD.
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•A one-pot derivatization/extraction method of furfurals was proposed.•PBH and MWCNTs were used for derivatization and extraction, respectively.•The derivatization extraction and ...steps were integrated into a single step.•On-pot simultaneous derivatization and extraction of three furfurals were realized.•The detection selectivity and accuracy were greatly improved.
Furfurals (5-hydroxymethylfurfural, furfural and 5-methyl furfural) have potential toxic effects to humans. This study developed a simple and rapid one-pot derivatization/extraction procedure for effective sample preparation of furfurals in complex samples prior to instrument analysis. The sample solution was incubated with 1-pyrenebutyric hydrazide (PBH) and hydroxyl-functionalized multi-walled carbon nanotubes (MWCNTs-OH) in a vial for 3 min. During this process, the furfurals were effectively derivatized by PBH and the furfural-PBH derivatives were selectively captured by MWCNTs-OH simultaneously. The detection selectivity and accuracy were greatly improved for the following liquid chromatography-tandem mass spectrometry analysis. Quantifying furfurals was validated over the 0.5–500 ng/mL concentration range with satisfactory linearities (R2 >0.99), accuracies (84.7%–119.0%) and precisions (<9.0%). The limits of quantification of 0.30, 0.36 and 0.20 ng/mL for 5-hydroxymethylfurfural, furfural and 5-methyl furfural, respectively, were achieved. Finally, the validated method was successfully applied to determine furfurals concentrations in various samples.
The clinical efficacy of cisplatin in the treatment of esophageal squamous cell carcinoma (ESCC) is undesirable. Signal transducer and activator of transcription 3β (STAT3β), a splice variant of ...STAT3, restrains STAT3α activity and enhances chemosensitivity in ESCC. However, the underlying molecular mechanisms remain poorly understood. Here, we found that high expression of STAT3β contributes to cisplatin sensitivity and enhances Gasdermin E (GSDME) dependent pyroptosis in ESCC cells after exposure to cisplatin. Mechanistically, STAT3β was located into the mitochondria and its high expression disrupts the activity of the electron transport chain, resulting in an increase of ROS in cisplatin treatment cells. While high levels of ROS caused activation of caspase-3 and GSDME, and induced cell pyroptosis. STAT3β blocked the phosphorylation of STAT3α S727 in mitochondria by interacting with ERK1/2 following cisplatin treatment, disrupting electron transport chain and inducing activation of GSDME. Clinically, high expression of both STAT3β and GSDME was strongly associated with better overall survival and disease-free survival of ESCC patients. Overall, our study reveals that STAT3β sensitizes ESCC cells to cisplatin by disrupting mitochondrial electron transport chain and enhancing pyroptosis, which demonstrates the prognostic significance of STAT3β in ESCC therapy.
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•The combination of STAT3β and GSDME as a biomarker to predict ESCC patient survival.•STAT3β enhances GSDME activation and pyroptosis after exposure to cisplatin.•STAT3β localizes to mitochondria and disrupts mitochondrial respiration.•STAT3β blocks the phosphorylation of STAT3α S727 by interacting with ERK1/2.
The purpose of this study was to use the complexes of gelatin (GA), positively charged arginine (Arg), and negatively charged aspartic acid (Asp) to produce a stable o/w emulsion using a low-energy ...stirring method. The thermal stability mechanism of this emulsion was investigated by evaluating its particle size, microstructure, differential scanning calorimetry (DSC), rheology, and ζ potential, as well as the secondary structure, surface hydrophobicity, and interaction force of gelatin-amino acid complexes. The results showed that adding Arg and/or Asp significantly decreased the particle size of the emulsion (P < 0.05). Particularly, the emulsion stabilized by gelatin-Arg-Asp showed the smallest particle size of 0.9 μm (D3.2), the highest absolute zeta potential (21.58 mV), the greatest viscosity, and the highest thermal stability. Even after heating at 121 °C for 20 min, this emulsion still had smaller particles than the unheated emulsion with or without Arg or Asp. Asp and Arg enhanced the triple helix content of gelatin through intramolecular hydrogen bonds and protected the surface hydrophobic groups of gelatins through intermolecular hydrophobic interactions of guanidine groups, increasing the depolymerization and ordered structure of gelatin and thus prolonging the temperature corresponding to the endothermic peak from 24.16 °C to 84.35 °C. These findings should contribute to the high thermal stability of the gelatin-Arg-Asp-stabilized emulsion. This study suggested that macromolecular protein-stabilized oil-in-water emulsions with a low oil phase content could be prepared by low-energy emulsification.
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•Heat-insensitive emulsions was prepared by low energy agitation.•The addition of Asp and Arg improved the thermal stability of emulsion.•The addition of Asp and Arg increased the triple helix level of gelatin.•The addition of Asp and Arg inhibited gelatin aggregation.•The aggregation relied heavily on hydrogen bonding and hydrophobic interactions.
•Clinical, serum proteomic, and radiomic data were integrated to develop classification models.•The models can accurately predict CCRT response of ESCC patients.•Nomogram models integrating ...multi-omics data achieved the best prediction performance.
Concurrent chemo-radiotherapy (CCRT) is the preferred non-surgical treatment for patients with locally advanced esophageal squamous cell carcinoma (ESCC). Unfortunately, some patients respond poorly, which leads to inappropriate or excessive treatment and affects patient survival. To accurately predict the response of ESCC patients to CCRT, we developed classification models based on the clinical, serum proteomic and radiomic data.
A total of 138 ESCC patients receiving CCRT were enrolled in this study and randomly split into a training cohort (n = 92) and a test cohort (n = 46). All patients were classified into either complete response (CR) or incomplete response (non-CR) groups according to RECIST1.1. Radiomic features were extracted by 3Dslicer. Serum proteomic data was obtained by Olink proximity extension assay. The logistic regression model with elastic-net penalty and the R-package “rms” v6.2–0 were applied to construct classification and nomogram models, respectively. The area under the receiver operating characteristic curves (AUC) was used to evaluate the predictive performance of the models.
Seven classification models based on multi-omics data were constructed, of which Model-COR, which integrates five clinical, five serum proteomic, and seven radiomic features, achieved the best predictive performance on the test cohort (AUC = 0.8357, 95 % CI: 0.7158–0.9556). Meanwhile, patients predicted to be CR by Model-COR showed significantly longer overall survival than those predicted to be non-CR in both cohorts (Log-rank P = 0.0014 and 0.027, respectively). Furthermore, two nomogram models based on multi-omics data also performed well in predicting response to CCRT (AUC = 0.8398 and 0.8483, respectively).
We developed and validated a multi-omics based classification model and two nomogram models for predicting the response of ESCC patients to CCRT, which achieved the best prediction performance by integrating clinical, serum Olink proteomic, and radiomic data. These models could be useful for personalized treatment decisions and more precise clinical radiotherapy and chemotherapy for ESCC patients.
Numerical simulations were carried out for moist, porous media, intermittent microwave convective drying (IMCD) using a multiphase flow model in porous media subdomains coupled with a ...forced-convection heat-transfer model in an external hot air subdomain. The models were solved by using COMSOL Multiphysics was applied at the pulse ratio (PR) of 3. Based on drying characteristics of porous media and the distribution of the evaporation interface, IMCD was compared with convection drying (CD). Drying uniformity K, velocity difference, temperature difference, and humidity difference were introduced to evaluate the performance of three models with different inlets and outlet wall curvature. The numerical results show that as the moisture content of slices was reduced to 3 kg/kg, the drying rate in IMCD was 0.0166–0.02 m/s higher than that in CD, and the total drying time of the former was 81.35% shorter than that of the latter. In the late drying stage of IMCD, the core of the sample still had a high vapor concentration and temperature, which led to the evaporation interface remaining on the surface. The vapor evaporated from the slices can diffuse rapidly to the outside, which is why IMCD is superior to traditional convection drying. Through the comprehensive analysis of the models with different inlet and outlet wall curvatures, the drying uniformity K of the type III was the highest, reaching 89.28%. Optimizing flow-field distribution can improve uniform of airflow distribution.
•Commercially available pyrene-1-boronic acid was effective to label catecholamines.•On-tissue labeling strategy was developed to label catecholamines in-situ.•The strategy succeeded in imaging ...catecholamines in adrenal gland tissue sections.•The strategy proved to be robust, easy-to-use and low-cost.•Distributions of catecholamines obtained by MALDI-MSI matched well optical images.
In this study, an on-tissue chemical labeling - matrix assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) method was developed for visualization of the distribution of three catecholamine (CA) compounds (dopamine, epinephrine and norepinephrine) in porcine adrenal gland. Commercially available pyrene-1-boronic acid (PBA) was employed as an effective in situ derivatizing reagent dissolved in acetonitrile containing 0.1% pyridine for the chemical labeling and the matrix coating. Without extra matrix coating, the tissue section was directly analyzed by MALDI-MS. The detection specificity and sensitivity were greatly improved with the on-tissue PBA labeling and successful imaging of the three CAs in porcine adrenal gland was achieved. Compared with previously reported methods for MALDI-MSI of the CAs, the analytical strategy proposed in the study provided a robust, easy-to-use and low-cost on-tissue chemical derivatization method that facilitated simultaneous molecular imaging of the three compounds.
Esophageal squamous cell carcinoma (ESCC) is one of the world's leading causes of death, and its primary clinical therapy relies on surgical resection, chemotherapy, radiotherapy, and ...chemoradiotherapy. Although the genomic features and clinical significance of ESCC have been identified, the outcomes of targeted therapies are still unsatisfactory. Here, we demonstrate that mitogen-activated protein kinase (MAPK) signaling is highly activated and associated with poor prognosis in patients with ESCC. Mitogen-activated protein kinase kinase (MEK) inhibitors efficiently blocked the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in ESCC, while signal transducer and activator of transcription 3 (STAT3) signaling was rapidly activated. Combined STAT3 inhibition prevented the emergence of resistance and enhanced MEK inhibitor-induced cell cycle arrest and senescence in vitro and in vivo. Mechanistic studies revealed that the suppressor of cytokine signaling 3 (SOCS3) was downregulated, resulting in an increase in STAT3 phosphorylation in MEK-inhibited cells. Furthermore, chromatin immunoprecipitation showed that ELK1, which was activated by MEK/ERK signaling, induced SOCS3 transcription. These data suggest that the development of combined MEK and STAT3 inhibition could be a useful strategy in ESCC targeted therapy.
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