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Molecules (Basel, Switzerland) Mar 2024The use of privileged scaffolds as a starting point for the construction of libraries of bioactive compounds is a widely used strategy in drug discovery and development....
The use of privileged scaffolds as a starting point for the construction of libraries of bioactive compounds is a widely used strategy in drug discovery and development. Scaffold decoration, morphing and hopping are additional techniques that enable the modification of the chosen privileged framework and better explore the chemical space around it. In this study, two series of highly functionalized pyrimidine and pyridine derivatives were synthesized using a scaffold morphing approach consisting of triazine compounds obtained previously as antiviral agents. Newly synthesized azines were evaluated against lymphoma, hepatocarcinoma, and colon epithelial carcinoma cells, showing in five cases acceptable to good anticancer activity associated with low cytotoxicity on healthy fibroblasts. Finally, ADME in vitro studies were conducted on the best derivatives of the two series showing good passive permeability and resistance to metabolic degradation.
Topics: Humans; Antineoplastic Agents; Antiviral Agents; Azo Compounds; Carcinoma, Hepatocellular; Liver Neoplasms
PubMed: 38611732
DOI: 10.3390/molecules29071452 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... Mar 2024To investigate the role of Rho/ROCK signaling pathway in mediating restraint stress-induced blood-brain barrier (BBB) injury in the amygdala of rats.
OBJECTIVE
To investigate the role of Rho/ROCK signaling pathway in mediating restraint stress-induced blood-brain barrier (BBB) injury in the amygdala of rats.
METHODS
Sixty male SD rats were randomized equally into control group (with food and water deprivation for 6 h per day), restraint stress group (with restraint for 6 h per day), stress + fasudil treatment (administered by intraperitoneal injection at 1 mg/100 g 30 min before the 6-h restraint) group, and fasudil treatment alone group. The elevated plus-maze test was used to detect behavioral changes of the rats, serum corticosterone and S100B levels were determined with ELISA, and Evans Blue leakage in the brain tissue was examined to evaluate the changes in BBB permeability. The changes in expression levels of tight junction proteins in the amygdala were detected using immunofluorescence assay and Western blotting, and Rho/ROCK pathway activation was detected by Pull-down test and Western blotting. Ultrastructural changes of the cerebral microvascular endothelial cells were observed using transmission electron microscopy.
RESULTS
Compared with those in the control group, the rats in restrain stress group and stress+fasudil group showed obvious anxiety-like behavior with significantly increased serum corticosterone level (<0.001). Compared with those in the control group and stress+fasudil group, the rat models of restrain stress showed more obvious Evans Blue leakage and higher S100B expression (<0.01) but lower expressions of tight junction proteins in the amygdala. Pull-down test and Western blotting confirmed that the expression levels of RhoA-GTP, ROCK2 and P-MLC 2 were significantly higher in stress group than in the control group and stress + fasudil group (<0.05). Transmission electron microscopy revealed obvious ultrastructural changes in the cerebral microvascular endothelial cells in the rat models of restrain stress.
CONCLUSION
Restraint stress induces BBB injury in the amygdala of rats by activating the Rho/ROCK signaling pathway.
Topics: Rats; Male; Animals; Blood-Brain Barrier; Rats, Sprague-Dawley; Evans Blue; Endothelial Cells; Corticosterone; Tight Junction Proteins; Signal Transduction; rho-Associated Kinases; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
PubMed: 38597431
DOI: 10.12122/j.issn.1673-4254.2024.03.01 -
RSC Advances Apr 2024A difficult issue in chemistry and materials science is to create metal compounds with well-defined components. Metal nanoclusters, particularly those of coinage groups... (Review)
Review
A difficult issue in chemistry and materials science is to create metal compounds with well-defined components. Metal nanoclusters, particularly those of coinage groups (Cu, Ag, and Au), have received considerable research interest in recent years owing to the availability of atomic-level precision joint experimental and theoretical methods, thus revealing the mechanisms in diverse nano-catalysts and functional materials. The textile sector significantly contributes to wastewater containing pollutants such as dyes and chemical substances. Textile and fabric manufacturing account for about 7 × 10 tons of wastewater annually. Approximately one thousand tons of dyes used in textile processing and finishing has been recorded as being discharged into natural streams and water bodies. Owing to the widespread environmental concerns, research has been conducted to develop absorbents that are capable of removing contaminants and heavy metals from water bodies using low-cost technology. Considering this idea, we reviewed coinage metal nanoclusters for azo and cationic dye degradation. Fluorometric and colorimetric techniques are used for dye degradation using coinage metal nanoclusters. Few reports are available on dye degradation using silver nanoclusters; and some of them are discussed in detailed herein to demonstrate the synergistic effect of gold and silver in dye degradation. Mostly, the Rhodamine B dye is degraded using coinage metals. Silver nanoclusters take less time for degradation than gold and copper nanoclusters. Mostly, HO is used for degradation in gold nanoclusters. Still, all coinage metal nanoclusters have been used for the degradation due to suitable HOMO-LUMO gap, and the adsorption of a dye onto the surface of the catalyst results in the exchange of electrons and holes, which leads to the oxidation and reduction of the adsorbed dye molecule. Compared to other coinage metal nanoclusters, Ag/g-CN nanoclusters displayed an excellent degradation rate constant with the dye Rhodamine B (0.0332 min). The behavior of doping transition metals in coinage metal nanoclusters is also reviewed herein. In addition, we discuss the mechanistic grounds for degradation, the fate of metal nanoclusters, anti-bacterial activity of nanoclusters, toxicity of dyes, and sensing of dyes.
PubMed: 38595712
DOI: 10.1039/d4ra00931b -
Scientific Reports Apr 2024The present study of a novel metal-organic framework containing Fe single atoms doped on electrospun carbon nanofibers (Fe SA-MOF@CNF) based on dispersive micro solid...
The present study of a novel metal-organic framework containing Fe single atoms doped on electrospun carbon nanofibers (Fe SA-MOF@CNF) based on dispersive micro solid phase extraction (D-μ-SPE) using HPLC-PDA for detection tartrazine in fake saffron samples was designed. The Fe SA-MOF@CNF sorbent was extensively characterized through various techniques including N adsorption-desorption isotherms, X-ray diffraction (XRD), scanning electron microscopy (SEM) and Fourier transform infrared (FTIR) spectroscopy. The specific area of surface of the sorbent was 577.384 m/g. The study variables were optimized via the central composite design (CCD), which included a sorbent mass of 15 mg, a contact time of 6 min, a pH of 7.56, and a tartrazine concentration of 300 ng/ml. Under the optimum condition, the calibration curve of this method was linear in the range of 5-1000 ng/mL, with a correlation coefficient of 0.992. The LOD and LOQ values were ranged 0.38-0.74 and 1.34-2.42 ng/ml, respectively. This approach revealed significant improvements, including high extraction recovery (98.64), recovery rates (98.43-102.72%), and accuracy (RSDs < 0.75 to 3.6%). the enrichment factors were obtained in the range of 80.6-86.4 with preconcentration factor of 22.3. Consequently, the D-μ-SPE method based on synthesized Fe SA-MOF@CNF could be recommended as a sustainable sorbent for detecting tartrazine in saffron samples.
Topics: Tartrazine; Metal-Organic Frameworks; Crocus; Chromatography, High Pressure Liquid; Solid Phase Extraction; Coloring Agents
PubMed: 38589481
DOI: 10.1038/s41598-024-58825-x -
Scientific Reports Apr 2024Phthorimaea absoluta is an invasive solanaceous plant pest with highly devastating effects on tomato plant. Heavy reliance on insecticide use to tackle the pest has been...
Phthorimaea absoluta is an invasive solanaceous plant pest with highly devastating effects on tomato plant. Heavy reliance on insecticide use to tackle the pest has been linked to insecticide resistance selection in P. absoluta populations. To underline insights on P. absoluta insecticide resistance mechanisms to diamides and avermectins, we evaluated the transcriptomic profile of parental (field-collected) and F8 (lab-reared) populations. Furthermore, to screen for the presence of organophosphate and pyrethroid resistance, we assessed the gene expression levels of acetylcholinesterase (ace1) and para-type voltage-gated sodium channel (VGSG) genes in the F1 to F8 lab-reared progeny of diamide and avermectin exposed P. absoluta field-collected populations. The VGSG gene showed up-regulation in 12.5% and down-regulation in 87.5% of the screened populations, while ace1 gene showed up-regulation in 37.5% and down-regulation in 62.5% of the screened populations. Gene ontology of the differentially expressed genes from both parental and eighth generations of diamide-sprayed P. absoluta populations revealed three genes involved in the metabolic detoxification of diamides in P. absoluta. Therefore, our study showed that the detoxification enzymes found could be responsible for P. absoluta diamide-based resistance, while behavioural resistance, which is stimulus-dependent, could be attributed to P. absoluta avermectin resistance.
Topics: Animals; Lepidoptera; Insecticides; Moths; Acetylcholinesterase; Diamide; Gene Expression Profiling; Larva; Ivermectin
PubMed: 38575641
DOI: 10.1038/s41598-024-58413-z -
BMC Oral Health Mar 2024Dental pulp stem cells (DPSCs) are a kind of undifferentiated dental mesenchymal stem cells with strong self-renewal ability and multi-differentiation potential. This...
BACKGROUND
Dental pulp stem cells (DPSCs) are a kind of undifferentiated dental mesenchymal stem cells with strong self-renewal ability and multi-differentiation potential. This study aimed to investigate the regulatory functions of succinylation modification in DPSCs.
METHODS
DPSCs were isolated from the dental pulp collected from healthy subjects, and then stem cell surface markers were identified using flow cytometry. The osteogenic differentiation ability of DPSCs was verified by alkaline phosphatase (ALP) and alizarin red staining methods, while adipogenic differentiation was detected by oil red O staining. Meanwhile, the mRNA of two desuccinylases (SIRT5 and SIRT7) and three succinylases (KAT2A, KAT3B, and CPT1A) in DPSCs before and after mineralization induction were detected using quantitative real-time PCR. The cell cycle was measured by flow cytometry, and the expression of bone-specific genes, including COL1a1 and Runx2 were evaluated by western blotting and were combined for the proliferation and differentiation of DPSCs. Co-immunoprecipitation (co-IP) and immunofluorescence were combined to verify the binding relationship between proteins.
RESULTS
The specific markers of mesenchymal stem cells were highly expressed in DPSCs, while the osteogenic differentiation ability of isolated DPSCs was confirmed via ALP and alizarin red staining. Similarly, the oil red O staining also verified the adipogenic differentiation ability of DPSCs. The levels of KAT2A were found to be significantly upregulated in mineralization induction, which significantly decreased the ratio of G0/G1 phase and increased S phase cells; converse results regarding cell cycle distribution were obtained when KAT2A was inhibited. Moreover, overexpression of KAT2A promoted the differentiation of DPSCs, while its inhibition exerted the opposite effect. The elevated KAT2A was found to activate the Notch1 signaling pathway, which succinylated Notch1 at the K2177 site to increase their corresponding protein levels in DPSCs. The co-IP results showed that KAT2A and Notch1 were endogenously bound to each other, while inhibition of Notch1 reversed the effects of KAT2A overexpression on the DPSCs proliferation and differentiation.
CONCLUSION
KAT2A interacted directly with Notch1, succinylating the Notch1 at the K2177 site to increase their corresponding protein levels in DPSCs. Similarly, KAT2A-mediated succinylation modification of Notch1 promotes the DPSCs proliferation and differentiation, suggesting that targeting KAT2A and Notch1 may contribute to tooth regeneration.
Topics: Humans; Osteogenesis; Stem Cells; Dental Pulp; Cell Proliferation; Cell Differentiation; Cells, Cultured; Histone Acetyltransferases; Anthraquinones; Azo Compounds
PubMed: 38556862
DOI: 10.1186/s12903-024-03951-1 -
Journal of Oleo Science 2024Infiltration of binary solution of hexane and ethanol into chromatography paper associated with their evaporation was found to generate unexpected initial rapid...
Infiltration of binary solution of hexane and ethanol into chromatography paper associated with their evaporation was found to generate unexpected initial rapid advancement of wicking front followed by its receding and readvancing in our previous research. In the present study, paper chromatography development of hydrophobic dye, Sudan III, and hydrophilic dye, Acid Blue 9, was carried out using binary solutions of hexane and ethanol in open environment, allowing the developing solvent been evaporated. Sudan III was developed with initial rapid advancing wicking front, while Acid Blue 9 was scarcely developed. On the other hand, Acid Blue 9 was developed with the readvancing second wicking front, while the spot of Sudan III scarcely migrated. Thus, the unexpected illusional phenomenon, overtaking the spot of Sudan III by the spot of Acid Blue 9, was observed. The readvancement of the second wicking front was found to be enhanced as increasing the relative humidity in the environment. Surface temperature of the chromatography paper was measured during the chromatographic development in open environment to show that it became lower than the dew point when the experiments were carried out in relatively high humidity. Solubility of Sudan III in a binary solution of ethanol and water remarkably decreased as increasing the content of water. It was thus suggested that the water vapor condensation to induce water mixing into the mobile phase to decrease the solubility of Sudan III to inhibit its chromatographic development to realize the illusional spot overtaking of dyes of their chromatographic development associated with solvent evaporation.
Topics: Coloring Agents; Solvents; Hexanes; Chromatography, High Pressure Liquid; Ethanol; Azo Compounds; Benzenesulfonates
PubMed: 38556292
DOI: 10.5650/jos.ess23235 -
Biomedical Research (Tokyo, Japan) 2024Although patients with chronic kidney disease (CKD) have a higher risk of colorectal cancer (CRC) aggravation, the connection between these two diseases is not well...
Although patients with chronic kidney disease (CKD) have a higher risk of colorectal cancer (CRC) aggravation, the connection between these two diseases is not well understood. Recent studies have shown that both CKD and CRC aggravation are closely related to an increased abundance of indole-producing Fusobacterium nucleatum in the gut. The indole absorbed from the gut is eventually metabolized to indoxyl sulfate in the liver. Since indoxyl sulfate is involved not only in accelerating CKD progression but also in the initiation and development of its associated complications, the present study aimed to clarify whether indoxyl sulfate induces the proliferation of CRC cells. This study found that indoxyl sulfate induced the proliferation of CRC-derived HCT-116 cells by activating the aryl hydrocarbon receptor (AhR) and the proto-oncogene Akt. The AhR antagonist CH223191 and Akt inhibitor MK2206 suppressed indoxyl sulfate-induced proliferation of HCT-116 cells. We also found that indoxyl sulfate upregulated epidermal growth factor receptor (EGFR) expression, which is associated with poor prognosis of CRC, whereas CH223191 and MK2206 repressed EGFR expression. Furthermore, indoxyl sulfate increased the sensitivity of CRC cells to EGF by upregulating EGFR expression. These findings suggest that indoxyl sulfate may be an important link between CKD and CRC aggravation.
Topics: Humans; Indican; Proto-Oncogene Proteins c-akt; Receptors, Aryl Hydrocarbon; ErbB Receptors; Indoles; Renal Insufficiency, Chronic; Cell Proliferation; Colorectal Neoplasms; Azo Compounds; Pyrazoles
PubMed: 38556263
DOI: 10.2220/biomedres.45.57 -
Nucleic Acids Research May 2024Pharmacological modulation of RNA splicing by small molecules is an emerging facet of drug discovery. In this context, the SMN2 splicing modifier SMN-C5 was used as a...
Pharmacological modulation of RNA splicing by small molecules is an emerging facet of drug discovery. In this context, the SMN2 splicing modifier SMN-C5 was used as a prototype to understand the mode of action of small molecule splicing modifiers and propose the concept of 5'-splice site bulge repair. In this study, we combined in vitro binding assays and structure determination by NMR spectroscopy to identify the binding modes of four other small molecule splicing modifiers that switch the splicing of either the SMN2 or the HTT gene. Here, we determined the solution structures of risdiplam, branaplam, SMN-CX and SMN-CY bound to the intermolecular RNA helix epitope containing an unpaired adenine within the G-2A-1G+1U+2 motif of the 5'-splice site. Despite notable differences in their scaffolds, risdiplam, SMN-CX, SMN-CY and branaplam contact the RNA epitope similarly to SMN-C5, suggesting that the 5'-splice site bulge repair mechanism can be generalised. These findings not only deepen our understanding of the chemical diversity of splicing modifiers that target A-1 bulged 5'-splice sites, but also identify common pharmacophores required for modulating 5'-splice site selection with small molecules.
Topics: Humans; Azo Compounds; Drug Design; Models, Molecular; Nucleic Acid Conformation; Pyrimidines; RNA Splice Sites; RNA Splicing; Survival of Motor Neuron 2 Protein
PubMed: 38554107
DOI: 10.1093/nar/gkae201 -
PloS One 2024The purpose of this study is to examine the possibility of GO to be used as an adsorbent for five novel potentially hazardous azo-dyes for their removal from aqueous...
The purpose of this study is to examine the possibility of GO to be used as an adsorbent for five novel potentially hazardous azo-dyes for their removal from aqueous solution. Adsorption characteristics of GO for azo-dyes removal were investigated by means of experimental and computational DFT as well as Monte Carlo approaches. Experimental studies include the effect of adsorbent dose, contact time, and initial concentration, while computational investigation involves DFT and Monte Carlo (MC) simulations. Through DFT studies geometric, electronic, and thermodynamic parameters were explored and possible mechanism of interactions and adsorption energies by predicted through MC by searching lowest possible adsorption complexes. Experimental data were evaluated by Langmuir models in order to describe the equilibrium isotherms. Equilibrium data fitted well to the Langmuir model. Thermodynamic parameters i.e., free energy change, enthalpy change, and entropy change revealed that the removal of azo-dyes by adsorption on the surface of GO molecular sieves was spontaneous. Nature of the process was found to be physiosorption involving non-covalent interaction. The study unveiled that GO can be used as an efficient adsorbent material for the adsorption of azo-dyes from aqueous solution.
Topics: Azo Compounds; Adsorption; Kinetics; Thermodynamics; Indicators and Reagents; Water; Coloring Agents; Water Pollutants, Chemical; Hydrogen-Ion Concentration
PubMed: 38551992
DOI: 10.1371/journal.pone.0299364