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Molecules (Basel, Switzerland) Apr 2024Alzheimer's disease (AD) is a complex neurodegenerative disease that can lead to the loss of cognitive function. The progression of AD is regulated by multiple signaling...
Alzheimer's disease (AD) is a complex neurodegenerative disease that can lead to the loss of cognitive function. The progression of AD is regulated by multiple signaling pathways and their associated targets. Therefore, multitarget strategies theoretically have greater potential for treating AD. In this work, a series of new hybrids were designed and synthesized by the hybridization of tacrine (, AChE: IC = 0.223 μM) with pyrimidone compound (GSK-3: IC = 3 μM) using the cysteamine or cystamine group as the connector. The biological evaluation results demonstrated that most of the compounds exhibited moderate to good inhibitory activities against acetylcholinesterase (AChE) and glycogen synthase kinase 3 (GSK-3). The optimal compound possessed potent dual AChE/GSK-3 inhibition (AChE: IC = 0.047 ± 0.002 μM, GSK-3: IC = 0.930 ± 0.080 μM). Further molecular docking and enzymatic kinetic studies revealed that this compound could occupy both the catalytic anionic site and the peripheral anionic site of AChE. The results also showed a lack of toxicity to SH-SY5Y neuroblastoma cells at concentrations of up to 25 μM. Collectively, this work explored the structure-activity relationships of novel tetrahydroacridin hybrids with sulfur-inserted linkers, providing a reference for the further research and development of new multitarget anti-AD drugs.
Topics: Alzheimer Disease; Humans; Cholinesterase Inhibitors; Acetylcholinesterase; Molecular Docking Simulation; Drug Design; Glycogen Synthase Kinase 3 beta; Cell Line, Tumor; Sulfur; Structure-Activity Relationship; Acridines; Tacrine; Molecular Structure
PubMed: 38675602
DOI: 10.3390/molecules29081782 -
Genes and Environment : the Official... Apr 2024An in vitro micronucleus assay is a standard genotoxicity test. Although the technique and interpretation of the results are simple, manual counting of the total and...
BACKGROUND
An in vitro micronucleus assay is a standard genotoxicity test. Although the technique and interpretation of the results are simple, manual counting of the total and micronucleus-containing cells in a microscopic field is tedious. To address this issue, several systems have been developed for quick and efficient micronucleus counting, including flow cytometry and automated detection based on specialized software and detection systems that analyze images.
RESULTS
Here, we present a simple and effective method for automated micronucleus counting using image recognition technology. Our process involves separating the RGB channels in a color micrograph of cells stained with acridine orange. The cell nuclei and micronuclei were detected by scaling the G image, whereas the cytoplasm was recognized from a composite image of the R and G images. Finally, we identified cells with overlapping cytoplasm and micronuclei as micronucleated cells, and the application displayed the number of micronucleated cells and the total number of cells. Our method yielded results that were comparable to manually measured values.
CONCLUSIONS
Our micronucleus detection (MN/cell detection software) system can accurately detect the total number of cells and micronucleus-forming cells in microscopic images with the same level of precision as achieved through manual counting. The accuracy of micronucleus numbers depends on the cell staining conditions; however, the software has options by which users can easily manually optimize parameters such as threshold, denoise, and binary to achieve the best results. The optimization process is easy to handle and requires less effort, making it an efficient way to obtain accurate results.
PubMed: 38659010
DOI: 10.1186/s41021-024-00305-9 -
Heliyon Apr 2024Inflammation affects several aspects of lung cancer progression including cell proliferation, metastasis, apoptosis, angiogenesis, and drug resistance. Baicalin, an...
Inflammation affects several aspects of lung cancer progression including cell proliferation, metastasis, apoptosis, angiogenesis, and drug resistance. Baicalin, an active component of Georgi, exhibits anticancer activity in various cancers. However, the effects of baicalin on lung cancer and the underlying molecular mechanisms remain largely unknown. This study is to explore the effect and mechanism of baicalin on lung cancer cell A549 and urethane-induced mouse lung cancer. A cell viability assay, colony formation assay, wound healing assay, acridine orange/ethidium bromide (AO/EB) staining assay, Western blot assay, urethane-induced mouse lung cancer model, hematoxylin and eosin (HE) staining, immunohistochemistry (IHC), and ELISA assay were performed to investigate the effects of baicalin on lung cancer and . Network pharmacology analysis, molecular docking, gene silencing assays, and LPS-induced inflammation model were utilized to explore the molecular mechanisms underlying the effect of baicalin on lung cancer. Baicalin showed significant anti-proliferative, anti-migratory, anti-inflammatory and pro-apoptotic effects ; it also inhibited the progression of urethane-induced mouse lung cancer . Mechanistically, suppressor of cytokine signaling 1 (SOCS1) was the key determinant for baicalin-induced inhibition of lung cancer. Baicalin increased SOCS1 expression to inactivate the NF-κB/STAT3 pathway to inhibit lung cancer and . Taken together, baicalin reduces inflammation to inhibit lung cancer via targeting SOCS1/NF-κB/STAT3 axis, providing a prospective compound and novel target for lung cancer treatment.
PubMed: 38628726
DOI: 10.1016/j.heliyon.2024.e29361 -
Scientific Reports Apr 2024A novel solid acid catalyst with recoverability, named as FeO@SiO@TAD-G2-SOH, was successfully synthesized by immobilizing sulfonic acid groups on triazine...
A novel solid acid catalyst with recoverability, named as FeO@SiO@TAD-G2-SOH, was successfully synthesized by immobilizing sulfonic acid groups on triazine dendrimer-modified magnetic nanoparticles. This nanomaterial structure and composition were thoroughly characterized using various analytical techniques, including thermogravimetric analysis (TGA), elemental analysis, Fourier transform infrared spectroscopy (FT-IR), energy-dispersive X-ray spectroscopy (EDX), elemental mapping, acid-base titration, X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and vibrating sample magnetometry (VSM). The acid-decorated magnetic dendrimer was served as a highly effective catalyst for the synthesis of tetrahydrobenzo[c]acridin-8(9H)-one and benzo[h]indeno[1,2-b]quinoline-8-one derivatives. The reaction proceeded smoothly under mild conditions through the one-pot condensation of aromatic aldehydes, 1-naphthylamine, and either dimedone or 1,3-indanedione, affording the desired products in high yields ranging from 90 to 96%. The catalyst was easily separated from the reaction mixture by employing a magnetic field, allowing for its recycling up to five times with slight loss in its activity (only 10%). Nearly, quantitative recovery of catalyst (up to 95%) could be obtained from each run. So, this catalyst facilitates the reaction progress and simplifies the purification process. Other remarkable features of this method are operational simplicity, excellent yields, mild condition, and a wide range of substrate applicability.
PubMed: 38627463
DOI: 10.1038/s41598-024-59212-2 -
Molecules (Basel, Switzerland) Mar 2024Easy-to-handle -hydroxyacridinecarbimidoyl chloride hydrochlorides were synthesized as convenient nitrile oxide precursors in the preparation of...
Easy-to-handle -hydroxyacridinecarbimidoyl chloride hydrochlorides were synthesized as convenient nitrile oxide precursors in the preparation of 3-(acridin-9/2-yl)isoxazole derivatives via 1,3-dipolar cycloaddition with terminal alkynes, 1,1-dichloroethene, and acrylonitrile. Azirines with an acridin-9/2-yl substituent attached directly or via the 1,2,3-triazole linker to the azirine C2 were also synthesized. The three-membered rings of the acridine-azirine hybrids were found to be resistant to irradiation in the UV/visible boundary region, despite their long-wave absorption at 320-420 nm, indicating that the acridine moiety cannot be used as an antenna to transfer light energy to generate nitrile ylides from azirines for photoclick cycloaddition. The acridine-isoxazole hybrids linked at the C9-C3 or C2-C3 atoms under blue light irradiation underwent the addition of such hydrogen donor solvents, such as, toluene, -xylene, mesitylene, 4-chlorotoluene, THF, 1,4-dioxane, or methyl -butyl ether (MTBE), to the acridine system to give the corresponding 9-substituted acridanes in good yields. The synthesized acridine-azirine, acridine-isoxazole, and acridane-isoxazole hybrids exhibited cytotoxicity toward both all tested cancer cell lines (HCT 116, MCF7, and A704) and normal cells (WI-26 VA4).
PubMed: 38611817
DOI: 10.3390/molecules29071538 -
Biochemical and Biophysical Research... May 2024P-glycoprotein (P-gp) is an ATP-binding cassette transporter known for its roles in expelling xenobiotic compounds from cells and contributing to cellular drug...
P-glycoprotein (P-gp) is an ATP-binding cassette transporter known for its roles in expelling xenobiotic compounds from cells and contributing to cellular drug resistance through multidrug efflux. This mechanism is particularly problematic in cancer cells, where it diminishes the therapeutic efficacy of anticancer drugs. P-gp inhibitors, such as elacridar, have been developed to circumvent the decrease in drug efficacy due to P-gp efflux. An earlier study reported the cryo-EM structure of human P-gp-Fab (MRK-16) complex bound by two elacridar molecules, at a resolution of 3.6 Å. In this study, we have obtained a higher resolution (2.5 Å) structure of the P-gp- Fab (UIC2) complex bound by three elacridar molecules. This finding, which exposes a larger space for compound-binding sites than previously acknowledged, has significant implications for the development of more selective inhibitors and enhances our understanding of the compound recognition mechanism of P-gp.
Topics: Humans; Acridines; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cryoelectron Microscopy; Tetrahydroisoquinolines
PubMed: 38579618
DOI: 10.1016/j.bbrc.2024.149855 -
RSC Advances Apr 2024In this study, we conveniently prepared a novel robust heterogeneous magnetic nanocatalyst using a FeO@SiO core/shell stabilized by gallic acid. The catalyst was...
FeO@SiO core/shell functionalized by gallic acid: a novel, robust, and water-compatible heterogeneous magnetic nanocatalyst for environmentally friendly synthesis of acridine-1,8-diones.
In this study, we conveniently prepared a novel robust heterogeneous magnetic nanocatalyst using a FeO@SiO core/shell stabilized by gallic acid. The catalyst was completely characterized by various physicochemical techniques, including infrared spectroscopy (FT-IR), X-ray diffraction (XRD), dynamic light scattering (DLS), transmission electron microscopy (TEM), field emission scanning electron microscopy (FE-SEM), thermogravimetric analysis (TGA), potentiometric titration, energy dispersive X-ray microanalysis (EDX), vibrating sample magnetometer (VSM), zeta potential analysis, and BET. The potential ability of the newly developed sulfonated nanocatalyst was then exploited in the multicomponent synthesis of acridine-1,8-dione derivatives by considering the green chemistry matrix and under mild conditions. Various aldehydes and amines were smoothly reacted with dimedone, affording the desired products in good to excellent yields. The introduction of sulfonic groups using gallic acid allowed the development of a water-compatible and highly recyclable catalytic system for reactions in an aqueous environment. The prepared catalyst can be readily magnetically separated and reused eight times without significant loss of activity. High synthetic efficiency, using a recyclable and eco-sustainable catalyst under mild conditions, and easy product isolation are salient features of this catalytic system, which makes this protocol compatible with the demands of green chemistry.
PubMed: 38577428
DOI: 10.1039/d4ra00629a -
BMC Microbiology Apr 2024Leishmaniasis as a neglected tropical disease (NTD) is caused by the inoculation of Leishmania parasites via the bite of phlebotomine sand flies. After an infected bite,...
BACKGROUND
Leishmaniasis as a neglected tropical disease (NTD) is caused by the inoculation of Leishmania parasites via the bite of phlebotomine sand flies. After an infected bite, a series of innate and adaptive immune responses occurs, among which neutrophils can be mentioned as the initiators. Among the multiple functions of these fighting cells, neutrophil extracellular traps (NETs) were studied in the presence of Leishmania major promastigotes and salivary gland homogenates (SGH) of Phlebotomus papatasi alone, and in combination to mimic natural conditions of transmission.
MATERIAL & METHODS
The effect of L. major and SGH on NETs formation was studied in three different groups: neutrophils + SGH (NS), neutrophils + L. major (NL), neutrophils + L. major + SGH (NLS) along with negative and positive controls in 2, 4 and 6 h post-incubation. Different microscopic methods were used to visualize NETs comprising: fluorescence microscopy by Acridine Orange/ Ethidium Bromide staining, optical microscopy by Giemsa staining and scanning electron microscopy. In addition, the expression level of three different genes NE, MPO and MMP9 was evaluated by Real-Time PCR.
RESULTS
All three microscopical methods revealed similar results, as in NS group, chromatin extrusion as a sign of NETosis, was not very evident in each three time points; but, in NL and especially NLS group, more NETosis was observed and the interaction between neutrophils and promastigotes in NL and also with saliva in NLS group, gradually increased over times. Real-time reveals that, the expression of MPO, NE and MMP9 genes increased during 2 and 4 h after exposure, and then decreased at 6 h in most groups.
CONCLUSION
Hence, it was determined that the simultaneous presence of parasite and saliva in NLS group has a greater impact on the formation of NETs compared to NL and NS groups.
Topics: Animals; Humans; Phlebotomus; Leishmania major; Matrix Metalloproteinase 9; Extracellular Traps; Neutrophils; Salivary Glands
PubMed: 38575882
DOI: 10.1186/s12866-024-03270-z -
Scientific Reports Apr 2024Efficient separation of electron-hole pairs remains pivotal in optimizing photogenerated carrier functionality across diverse catalytic and optoelectronic systems. This...
Efficient separation of electron-hole pairs remains pivotal in optimizing photogenerated carrier functionality across diverse catalytic and optoelectronic systems. This study presents the fabrication of a novel hollow direct Z-scheme photocatalyst, ZnO/TiO. A thorough analysis encompassing various techniques such as Ultraviolet-Visible Spectroscopy (UV-Vis), X-ray Diffraction (XRD), Transmission electron Microscopy (TEM), Fourier Transform Infrared Spectroscopy (FT-IR), Thermogravimetric Analysis (TGA), and Energy-Dispersive X-ray Spectroscopy (EDX) provided detailed insights into the complex material characteristics of the ZnO/TiO heterojunction catalyst. The findings revealed coexisting anatase TiO and wurtzite ZnO phases, each retaining distinct attributes within the nanocomposites (NCs) structure. The study showcased the photocatalytic efficacy of ZnO/TiO-NCs in decomposing Methylene Blue and Acridine Orange under UV irradiation, correlated with their underlying structures. Enhanced degradation of these dyes resulted from the establishment of a direct Z-scheme heterojunction between ZnO and TiO. Employing Density Functional Theory (DFT) using Quantum ESPRESSO, this research analyzed phase diagrams and band structures, elucidating electronic properties and structural correlations. The study characterized a ZnO/TiO composite, revealing a band gap of 3.1-3.3 eV through UV-Visible spectroscopy and confirming its formation without impurity phases via XRD analysis. TEM and EDX showed uniform element dispersion (Zn: 27%, Ti: 29.62%, C: 5.03%, O: 38.35%). Computational analysis using DFT indicated a reduction in stable phases with increasing temperature. Enhanced dye degradation was observed (MB: 88.9%, AO: 84%), alongside significant antibacterial activity. In the future we predict that research will focus on development of scaled up production and photocatalytic activity through surface modification, while unveiling mechanistic insights and environmental applicability for multifunctional use in water treatment and antibacterial applications, leading to further advancement of the field.
PubMed: 38575610
DOI: 10.1038/s41598-024-57392-5 -
Biomedicine & Pharmacotherapy =... May 2024Diabetic nephropathy is a type of kidney disorder that develops as a complication of multifactorial diabetes. Diabetic nephropathy is characterized by microangiopathy,...
INTRODUCTION
Diabetic nephropathy is a type of kidney disorder that develops as a complication of multifactorial diabetes. Diabetic nephropathy is characterized by microangiopathy, resulting from glucose metabolism, oxidative stress, and changes in renal hemodynamics. This study strived to evaluate the in vitro cytoprotective activity of atorvastatin (ATR), and quercetin (QCT) alone and in combination against diabetic nephropathy.
METHODS
The MTT assay was utilized to analyze the effects of the test compounds on NRK-52E rat kidney epithelial cells. The detection of apoptosis and ability to scavenge free radicals was assessed via acridine orange-ethidium bromide (AO-EB) dual fluorescence staining, and 2,2-diphenyl-1-picrylhydrazyfree assay (DPPH), respectively. The ability of anti-inflammatory effect of the test compounds and western blot analysis against TGF-β, TNF-α, and IL-6 further assessed to determine the combinatorial efficacy.
RESULTS
Atorvastatin and quercetin treatment significantly lowered the expression of TGF-β, TNF-α, and IL-6 indicating the protective role in Streptozotocin-induced nephrotoxicity. The kidney cells treated with a combination of atorvastatin and quercetin showed green fluorescing nuclei in the AO-EB staining assay, indicating that the combination treatment restored cell viability. Quercetin, both alone and in combination with atorvastatin, demonstrated strong DPPH free radical scavenging activity and further encountered an anti-oxidant and anti-inflammatory effect on the combination of these drugs.
CONCLUSION
Nevertheless, there is currently no existing literature that reports on the role of QCT as a combination renoprotective drug with statins in the context of diabetic nephropathy. Hence, these findings suggest that atorvastatin and quercetin may have clinical potential in treating diabetic nephropathy.
Topics: Quercetin; Atorvastatin; Animals; Diabetic Nephropathies; Rats; Cell Line; Apoptosis; Antioxidants; Kidney; Transforming Growth Factor beta; Drug Therapy, Combination; Cell Survival; Oxidative Stress; Anti-Inflammatory Agents
PubMed: 38574626
DOI: 10.1016/j.biopha.2024.116533