ChK1 activation induces reactive astrogliosis through CIP2A/PP2A/STAT3 pathway in Alzheimer's disease.

Cancerous Inhibitor of PP2A (CIP2A), an endogenous PP2A inhibitor, is upregulated and causes reactive astrogliosis, synaptic degeneration, and cognitive deficits in Alzheimer's disease (AD). However, the mechanism underlying the increased CIP2A expression in AD brains remains unclear. We here demonstrated that the DNA damage-related Checkpoint kinase 1 (ChK1) is activated in AD human brains and 3xTg-AD mice. ChK1-mediated CIP2A overexpression drives inhibition of PP2A and activates STAT3, then leads to reactive astrogliosis and neurodegeneration in vitro. Infection of mouse brain with GFAP-ChK1-AAV induced AD-like cognitive deficits and exacerbated AD pathologies in vivo. In conclusion, we showed that ChK1 activation induces reactive astrogliosis, degeneration of neurons, and exacerbation of AD through the CIP2A-PP2A-STAT3 pathway, and inhibiting ChK1 may be a potential therapeutic approach for AD treatment.

An enhanced machine learning approach for effective prediction of IgA nephropathy patients with severe proteinuria based on clinical data.

IgA Nephropathy (IgAN) is a disease of the glomeruli that may eventually lead to chronic kidney disease or kidney failure. The signs and symptoms of IgAN nephropathy are usually not specific enough and are similar to those of other glomerular or inflammatory diseases. This makes a correct diagnosis more difficult. This study collected data from a sample of adult patients diagnosed with primary IgAN at the First Affiliated Hospital of Wenzhou Medical University, with proteinuria ≥1 g/d at the time of diagnosis. Based on these samples, we propose a machine learning framework based on weIghted meaN oF vectOrs (INFO). An enhanced COINFO algorithm is proposed by merging INFO, Cauchy Mutation (CM) and Oppositional-based Learning (OBL) strategies. At the same time, COINFO and Support Vector Machine (SVM) were integrated to construct the BCOINFO-SVM framework for IgAN diagnosis and prediction. Initially, the proposed enhanced COINFO is evaluated using the IEEE CEC2017 benchmark problems, with the outcomes demonstrating its efficient optimization capability and accuracy in convergence. Furthermore, the feature selection capability of the proposed method is verified on the public medical datasets. Finally, the auxiliary diagnostic experiment was carried out through IgAN real sample data. The results demonstrate that the proposed BCOINFO-SVM can screen out essential features such as High-Density Lipoprotein (HDL), Uric Acid (UA), Cardiovascular Disease (CVD), Hypertension and Diabetes. Simultaneously, the BCOINFO-SVM model achieves an accuracy of 98.56%, with sensitivity at 96.08% and specificity at 97.73%, making it a potential auxiliary diagnostic model for IgAN.

Bioactivity, Uptake, and Distribution of Prothioconazole Loaded on Fluorescent Double-Hollow Shelled Mesoporous Silica in Soybean Plants.

Prothioconazole (PTC) has been widely utilized for plant fungal disease control, but its metabolite prothioconazole-desthio (PTC-d) exhibits reproductive toxicity. In the present study, carbon quantum dot (CQD)-modified fluorescent double-hollow shelled mesoporous silica nanoparticles (FL-MSNs) loaded with PTC, referred to as PTC@FL-MSNs, were constructed with an average size of 369 nm and a loading capacity of 28.1 wt %, which could increase the antifungal efficiency of PTC. In addition, upright fluorescence microscope and UPLC-MS/MS studies showed that PTC@FL-MSNs could be effectively transported via root uptake and foliar spray in soybean plants. Compared to a 30% PTC dispersible oil suspension agent, the PTC@FL-MSN treatment group showed higher concentrations (leaves: 0.50 > 0.48 mg/kg), longer half-lives for degradation (leaves: 3.62 > 3.21 d; roots: 3.39 > 2.82 d), and fewer metabolites. These findings suggest that sustained pesticide release and toxicity reduction are potential applications for PTC nanofungicide delivery technology.

Comparison of the interactions of flupyrimin and nitenpyram with serum albumins via multiple analysis methods.

Flupyrimin and nitenpyram are emerging neonicotinoid insecticides that may cause potential harm to the human body. In the present work, the interactions of flupyrimin/nitenpyram with serum albumins under normal physiological conditions were thoroughly studied by using multiple spectroscopic techniques, DFT calculations and molecular docking. Flupyrimin/nitenpyram can quench the endogenous fluorescence of HSA/BSA and form a complex with HSA/BSA through a static process, causing conformational and secondary structure changes of HSA/BSA. Thermodynamic analysis shows that the combination of flupyrimin/nitenpyram with HSA/BSA is a spontaneous process, mainly driven by hydrogen bonds and hydrophobic forces. Site marking and molecular docking experiments indicated that flupyrimin/nitenpyram binds with HSA/BSA at site II (subdomain IIIA). The binding constant Ka in HSA-flupyrimin, HSA-nitenpyram, BSA-flupyrimin and BSA-nitenpyram systems at 298 K was 2.11 × 105 M-1, 2.35 × 105 M-1, 1.91 × 105 M-1 and 2.11 × 105 M-1, respectively. The binding constant Ka of nitenpyram with HSA/BSA was greater than flupyrimin, indicating that nitenpyram binds HSA/BSA was more stable than that of flupyrimin, which was consistent with the DFT calculation. In addition, the acute toxicity bioassay showed that flupyrimin and nitenpyram exhibited low toxicity to zebrafish, with 96 h LC50 values of 181.662 and 250.658 mg a. i. L-1, respectively. These results can help understand the interactions of flupyrimin/nitenpyram with HSA/BSA.

New insights into the interactions between humic acid and three neonicotinoid pesticides, with multiple spectroscopy technologies, two-dimensional correlation spectroscopy analysis and density functional theory.

The widespread use of neonicotinoid pesticides in agricultural production has caused pressure on the environment. In the present work, the interactions between humic acid (HA) and three neonicotinoid insecticides, dinotefuran, clothianidin and nitenpyram, were investigated by using multiple spectroscopy techniques combined with two-dimensional correlation spectroscopy analysis and density functional theory (DFT). Dinotefuran, clothianidin and nitenpyram could quench the endogenous fluorescence of HA through a static quenching process dominated by hydrogen bonds and van der Waals forces. According to the revised Stern-Volmer equation and DFT calculation, the binding abilities of the three pesticides with HA were ranked as dinotefuran < clothianidin < nitenpyram. The results of dynamic light scattering showed that neutral conditions were more conducive to the combination of HA and dinotefuran, clothianidin and nitenpyram. Through Fourier transform infrared spectroscopy (FTIR) combined with two-dimensional correlation analysis (2D-COS), the functional group with the strongest binding ability in the HA-dinotefuran, HA-clothianidin and HA-nitenpyram system was CH, CO and CO, respectively. The work will help to further understand the behavior of neonicotinoid pesticides in the environment.

A novel near-infrared fluorimetric method for point-of-care monitoring of Fe2+ and its application in bioimaging.

Iron is one of the essential trace elements in the human body, which is involved in many important physiological processes of life. The abnormal amount of iron in the body will bring many diseases. Therefore, a novel near-infrared fluorimetric method was developed. The method is based on a fluorescent probe (E)-4-(2-(3-(dicyanomethylene)-5,5-dimethylcyclohex-1-en-1-yl)vinyl)-N, N-diethylaniline oxide (DDED) which uses N-oxide as a recognition group to real-time monitoring and imaging of Fe2+ in vivo and in vitro. The method exhibits excellent selectivity and high sensitivity (LOD = 27 nM) for Fe2+, fast reaction rate (< 4 min), extremely large Stokes shift (＞ 275 nm), low cytotoxicity. The strip test strongly illustrates the potential application of DDED in real environment. In particular, DDED has been successfully applied to real-time monitoring and imaging of Fe2+ in HepG2 cells and zebrafish. That is, the method has great potential for the detection of Fe2+ in living systems.

Hydrazine exposure: A near-infrared ICT-based fluorescent probe and its application in bioimaging and sewage analysis.

Hydrazine (N2H4) is an environment pollutant with high acute toxicity and potential carcinogenicity, and detection of N2H4 has attracted increasing attention. In the present study, a low toxicity near-infrared fluorescent probe (DCDB) based on the intramolecular charge transfer (ICT) principle was developed. The probe DCDB exhibits excellent selectivity and high sensitivity (LOD = 1.27 ppb) for N2H4, fast reaction rate (5 min), extremely large Stokes shift (160 nm). The color transformation of the DCDB-N2H4 system from purple to pink can be observed with the naked eye. The success of N2H4 test strips to detect trace N2H4 in actual sewage strongly illustrates the practical application potential of DCDB. Importantly, DCDB can be utilized to monitor the distribution of exogenous N2H4 in vivo and in vitro.

Interactions between Imidacloprid and Thiamethoxam and Dissolved Organic Matter Characterized by Two-Dimensional Correlation Spectroscopy Analysis, Molecular Modeling, and Density Functional Theory Calculations.

The heavy application of neonicotinoid insecticides in agricultural production has burdened the environment. In the present study, interactions of two neonicotinoid insecticides imidacloprid and thiamethoxam with dissolved organic matter (DOM) were investigated by spectroscopic techniques, molecular modeling, and density functional theory (DFT) calculations. The static mechanism of imidacloprid and thiamethoxam quenching the endogenous fluorescence of DOM was assessed through time-resolved analyses. During the binding process, a protein-like substance binds imidacloprid and thiamethoxam later than a humic-like substance, as analyzed by two-dimensional correlation spectroscopy, but more strongly than the humic-like substance, as suggested by molecular modeling and DFT calculations. The conformational changes of DOM are attributed to imidacloprid and thiamethoxam, as assessed with three-dimensional spectra. Fourier transform infrared spectroscopy indicated that DOM binds imidacloprid and thiamethoxam by hydroxyl, aliphatic C-H, amide I, and carboxyl to form stable DOM-imidacloprid and DOM-thiamethoxam complexes. Understanding the changes in the structural conformation of humic-like and protein-like substances with imidacloprid and thiamethoxam helps further understand the fate of the neonicotinoids in the environment.

An ICT-based fluorescent probe with a large Stokes shift for measuring hydrazine in biological and water samples.

As a strong reductant and highly active alkali, hydrazine (N2H4) has been widely used in chemical industry, pharmaceutical manufacturing and agricultural production. However, its high acute toxicity poses a threat to ecosystem and human health. In the present study, a ratiometric fluorescent probe for the detection of N2H4 was designed, utilizing dicyanoisophorone as the fluorescent group and 4-bromobutyryl moiety as the recognition site. 4-(2-(3-(dicyanomethylene)-5,5-dimethylcyclohex-1-enyl) phenyl 4-brobutanoate (DDPB) was readily synthesized and could specially sense N2H4 via an intramolecular charge transfer (ICT) pathway. The cyclization cleavage reaction of N2H4 with a 4-bromobutyryl group released phenolic hydroxyl group and reversed the ICT process between hydroxy group and fluorophore, turning on the fluorescence in the DDPB-N2H4 complexes. DDPB exhibits a low cytotoxicity, reasonable cell permeability, a large Stokes shift (186 nm) and a low detection limit (86.3 nM). The quantitative determination of environmental water systems and the visualization fluorescence of DDPB test strips provides a strong evidence for the applications of DDPB. In addition, DDPB is suitable for the fluorescence imaging of exogenous N2H4 in HeLa cells and zebrafish.