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Bioorganic Chemistry Aug 2024Targeting protein kinases that regulate signalling pathways in inflammation is an effective pharmacological approach to alleviate uncontrolled inflammatory diseases. In...
Targeting protein kinases that regulate signalling pathways in inflammation is an effective pharmacological approach to alleviate uncontrolled inflammatory diseases. In this context, the natural product indirubin and its 6-bromo-substituted analogue 6-bromoindirubin-3 -glycerol-oxime ether (6BIGOE; 1) were identified as potent inhibitors of glycogen synthase kinase-3β (GSK-3β). These inhibitors suppress the release of pro-inflammatory cytokines and prostaglandins (PG) from human monocytes. However, indirubin derivatives target several protein kinases such as cyclin-dependent kinases (CDKs) which has been a major concern for their application in inflammation therapy. Here, we report on a library of 13 5-bromo-substituted indirubin derivatives that have been designed to improve potency and target selectivity. Side-by-side comparison of reference compound 1 (6BIGOE) with 5-bromo derivatives revealed its isomer 2 (5BIGOE), as the most potent derivative able to supress pro-inflammatory cytokine and PG release in lipopolysaccharide-stimulated human monocytes. Analysis of protein kinase inhibition in intact monocytes, supported by our in silico findings, proposed higher selectivity of 1 for GSK-3β inhibition with lesser potency against CDKs 8 and 9. In contrast, 2 supressed the activity of these CDKs with higher effectiveness than GSK-3β, representing additional targets of indirubins within the inflammatory response. Encapsulation of 1 and 2 into polymer-based nanoparticles (NP) improved their pharmacological potential. In conclusion, the 5- and 6-brominated indirubins 1 and 2 as dual GSK-3β and CDK8/9 inhibitors represent a novel concept for intervention with inflammatory disorders.
Topics: Humans; Monocytes; Indoles; Protein Kinase Inhibitors; Signal Transduction; Structure-Activity Relationship; Molecular Structure; Inflammation Mediators; Dose-Response Relationship, Drug; Lipopolysaccharides; Cytokines; Molecular Docking Simulation
PubMed: 38838619
DOI: 10.1016/j.bioorg.2024.107470 -
RSC Advances May 2024The current investigation centers on elucidating the intricate molecular architecture and dynamic behavior of four macrolide antibiotics, specifically erythromycin,...
The current investigation centers on elucidating the intricate molecular architecture and dynamic behavior of four macrolide antibiotics, specifically erythromycin, clarithromycin, azithromycin, and roxithromycin, through the application of sophisticated solid-state nuclear magnetic resonance (SSNMR) methodologies. We have measured the principal components of chemical shift anisotropy (CSA) parameters, and the site-specific spin-lattice relaxation time at carbon nuclei sites. To extract the principal components of CSA parameters, we have employed C 2DPASS CP-MAS SSNMR experiments at two different values of magic angle spinning (MAS) frequencies, namely 2 kHz and 600 Hz. Additionally, the spatial correlation between C and H nuclei has been investigated using H-C frequency switched Lee-Goldburg heteronuclear correlation (FSLGHETCOR) experiment at a MAS frequency of 24 kHz. Our findings demonstrate that the incorporation of diverse functional groups, such as the ketone group and oxime group with the lactone ring, exerts notable influences on the structure and dynamics of the macrolide antibiotic. In particular, we have observed a significant decrease in the spin-lattice relaxation time of carbon nuclei residing on the lactone ring, desosamine, and cladinose in roxithromycin, compared to erythromycin. Overall, our findings provide detailed insight into the relationship between the structure and dynamics of macrolide antibiotics, which is eventually correlated with their biological activity. This knowledge can be utilized to develop new and more effective drugs by providing a rational basis for drug discovery and design.
PubMed: 38832242
DOI: 10.1039/d4ra00718b -
Translational Psychiatry Jun 2024Prior regional Cerebral Blood Flow (rCBF) studies in Major Depressive Disorder (MDD) have been limited by small, highly selective, non-representative samples that have...
Prior regional Cerebral Blood Flow (rCBF) studies in Major Depressive Disorder (MDD) have been limited by small, highly selective, non-representative samples that have yielded variable and poorly replicated findings. The aim of this study was to compare rCBF measures in a large, more representative community sample of adults with MDD and healthy control participants. This is a cross-sectional, retrospective multi-site cohort study in which clinical data from 338 patients 18-65 years of age with a primary diagnosis of MDD were retrieved from a central database for 8 privately owned, private-pay outpatient psychiatric centers across the United States. Two Tc-HMPAO SPECT brain scans, one at rest and one during performance of a continuous performance task, were acquired as a routine component of their initial clinical evaluation. In total, 103 healthy controls, 18-65 years old and recruited from the community were also assessed and scanned. Depressed patients had significantly higher rCBF in frontal, anterior cingulate, and association cortices, and in basal ganglia, thalamus, and cerebellum, after accounting for significantly higher overall CBF. Depression severity associated positively with rCBF in the basal ganglia, hippocampus, cerebellum, and posterior white matter. Elevated rCBF was especially prominent in women and older patients. Elevated rCBF likely represents pathogenic hypermetabolism in MDD, with its magnitude in direct proportion to depression severity. It is brain-wide, with disproportionate increases in cortical and subcortical attentional networks. Hypermetabolism may be a reasonable target for novel therapeutics in MDD.
Topics: Humans; Depressive Disorder, Major; Adult; Female; Male; Middle Aged; Cerebrovascular Circulation; Cross-Sectional Studies; Tomography, Emission-Computed, Single-Photon; Young Adult; Retrospective Studies; Adolescent; Technetium Tc 99m Exametazime; Brain; Aged; Radiopharmaceuticals
PubMed: 38830866
DOI: 10.1038/s41398-024-02961-5 -
Journal of Agricultural and Food... Jun 2024Iron is an essential element in the composition of living organisms and plays a crucial role in a wide range of biological activities. The human body primarily obtains...
Iron is an essential element in the composition of living organisms and plays a crucial role in a wide range of biological activities. The human body primarily obtains essential iron through the consumption of food. Therefore, it is vital for the health of human body to maintain iron homeostasis. The reducing character of the cellular microenvironment enables Fe to occupy a dominant position within the cell. Hence, there is an urgent need for a simple and sensitive tool that can detect a large amount of Fe in organisms. In this work, a highly specific fluorescent chemodosimeter ("NP" represents the naphthalimide fluorophore, and "CO" represents the carbamoyl oxime structure) for the detection of Fe with excellent sensitivity (LOD = 82 nM) was constructed by incorporating a novel carbamoyl oxime structure as the recognition group. can be effectively employed for the detection of Fe in food samples, living cells, and zebrafish. Furthermore, by using soybean sprouts as a model plant, the application of was expanded to detect Fe in plants. Therefore, could be used as an excellent assay tool for detecting Fe in organisms and is expected to be an important aid in exploring the mechanism of iron regulation.
Topics: Fluorescent Dyes; Humans; Animals; Iron; Oximes; Zebrafish
PubMed: 38830118
DOI: 10.1021/acs.jafc.4c04108 -
Reviews in Medical Virology Jul 2024
Topics: Humans; COVID-19 Drug Treatment; Fluvoxamine; COVID-19; SARS-CoV-2; Post-Acute COVID-19 Syndrome; Selective Serotonin Reuptake Inhibitors
PubMed: 38825753
DOI: 10.1002/rmv.2557 -
International Journal of Biological... Jun 2024Uranium as a nuclear fuel, its source and aftertreatment has been a hot topic of debate for developers. In this paper, amidoxime and guanidino-modified cotton fibers...
Uranium as a nuclear fuel, its source and aftertreatment has been a hot topic of debate for developers. In this paper, amidoxime and guanidino-modified cotton fibers (DC-AO-PHMG) were synthesized by the two-step functionalization approach, which exhibited remarkable antimicrobial and high uranium recovery property. Adsorption tests revealed that DC-AO-PHMG had excellent selectivity and anti-interference properties, the maximum adsorption capacity of 609.75 mg/g. More than 85 % adsorption capacity could still be kept after 10 adsorption-desorption cycles, and it conformed to the pseudo-second-order kinetic model and the Langmuir adsorption isotherm model as a spontaneous heat-absorbing chemical monolayer process. FT-IR, EDS and XPS analyses speculated that the amidoxime and amino synergistically increased the uranium uptake. The inhibitory activities of DC-AO-PHMG against three aquatic bacteria, BEY, BEL (from Yellow River water and lake bottom silt, respectively) and B. subtilis were significantly stronger, and the uranium adsorption was not impacted by the high bacteria content. Most importantly, DC-AO-PHMG removed up to 94 % of uranium in simulated seawater and extracted up to 4.65 mg/g of uranium from Salt Lake water, which demonstrated its great potential in the field of uranium resource recovery.
Topics: Uranium; Adsorption; Cotton Fiber; Oximes; Sewage; Kinetics; Anti-Bacterial Agents; Water Purification
PubMed: 38823750
DOI: 10.1016/j.ijbiomac.2024.132776 -
Spectrochimica Acta. Part A, Molecular... Oct 2024It is crucial to identify aberrant HClO levels in living things since they pose a major health risk and are a frequent reactive oxygen species (ROS) in living organisms....
It is crucial to identify aberrant HClO levels in living things since they pose a major health risk and are a frequent reactive oxygen species (ROS) in living organisms. In order to detect HClO in various biological systems, we created and synthesized a near-infrared fluorescent probe with an oxime group (-C = N-OH) as a recognition unit. The probe DCMP1 has the advantages of fast response (10 min), near-infrared emission (660 nm), large Stokes shift (170 nm) and high selectivity. This probe DCMP1 not only detects endogenous HClO in living cells, but also enables further fluorescence detection of HClO in living zebrafish. More importantly, it can also be used for fluorescence imaging of HClO in an rheumatoid arthritis mouse model. This fluorescent probe DCMP1 is anticipated to be an effective tool for researching HClO.
Topics: Animals; Fluorescent Dyes; Hypochlorous Acid; Zebrafish; Arthritis, Rheumatoid; Mice; Humans; Disease Models, Animal; Optical Imaging; Spectrometry, Fluorescence
PubMed: 38823237
DOI: 10.1016/j.saa.2024.124547 -
Anticancer Research Jun 2024Approximately 50% of melanomas harbor the BRAF V600E mutation and targeted therapies using BRAF inhibitors improve patient outcomes. Nonetheless, resistance to BRAF...
BACKGROUND/AIM
Approximately 50% of melanomas harbor the BRAF V600E mutation and targeted therapies using BRAF inhibitors improve patient outcomes. Nonetheless, resistance to BRAF inhibitors develops rapidly and remains a challenge in melanoma treatment. In this study, we attempted to isolate long noncoding RNAs (lncRNAs) involved in BRAF inhibitor resistance using a comprehensive screening method.
MATERIALS AND METHODS
We used a CRISPR-Cas9 synergistic activation mediator (SAM) protein complex in a genome-scale transcriptional activation assay to screen for candidate lncRNA genes related to BRAF inhibitor resistance. Correlation analysis was performed between expression levels of isolated lncRNA genes and IC of dabrafenib in a BRAF-mutated melanoma cell line. Next, online databases were used to construct the lncRNA-miRNA-mRNA regulatory network. Finally, we evaluated the significance of the expression levels of these lncRNAs and mRNAs as biomarkers using clinical specimens.
RESULTS
We isolated three BRAF inhibitor resistance-associated lncRNA genes, namely SNHG16, NDUFV2-AS1, and LINC01502. We constructed a lncRNA-miRNA-mRNA network of 13 nodes consisting of three lncRNAs, six miRNAs, and four mRNAs. The lncRNAs and target mRNAs from each regulatory axis significantly and positively correlated with each other. Finally, Kaplan-Meier analysis showed that higher expression levels of MITF, which was up-regulated by LINC01502, were significantly associated with worse prognosis in BRAF V600E-mutated melanoma.
CONCLUSION
The identification of these BRAF inhibitor resistance-associated lncRNA genes at the genomic scale and the establishment of the lncRNA-miRNA-mRNA regulatory network provides new insights into the underlying mechanisms of BRAF inhibitor resistance in melanoma.
Topics: Humans; Proto-Oncogene Proteins B-raf; RNA, Long Noncoding; Drug Resistance, Neoplasm; CRISPR-Cas Systems; Melanoma; Cell Line, Tumor; Transcriptional Activation; Protein Kinase Inhibitors; Gene Expression Regulation, Neoplastic; Imidazoles; Mutation; Oximes; RNA, Messenger; Gene Regulatory Networks
PubMed: 38821628
DOI: 10.21873/anticanres.17042 -
Journal of Agricultural and Food... Jun 2024Protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) is one of the most important targets for the discovery of green herbicides. In order to find novel PPO inhibitors with a...
Protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) is one of the most important targets for the discovery of green herbicides. In order to find novel PPO inhibitors with a higher herbicidal activity, a series of novel -phenyltriazinone derivatives containing oxime ether and oxime ester groups were designed and synthesized based on the strategy of pharmacophore and scaffold hopping. Bioassay results revealed that some compounds showed herbicidal activities; especially, compound exhibited broad-spectrum and excellent 100% herbicidal effects to , , , , , and at a concentration of 37.5 g a.i./ha, which were comparable to trifludimoxazin. PPO (PPO) enzyme inhibitory assay indicated that showed an excellent enzyme inhibitory activity with a value of 32.14 nM, which was similar to that of trifludimoxazin (31.33 nM). Meanwhile, compound revealed more safety for crops (rice, maize, wheat, peanut, soybean, and cotton) than trifludimoxazin at a dose of 150 g a.i./ha. Moreover, molecular docking and molecular dynamics simulation further showed that has a very strong and stable binding to PPO. It indicated that can be used as a potential PPO inhibitor and herbicide candidate for application in the field.
Topics: Protoporphyrinogen Oxidase; Herbicides; Enzyme Inhibitors; Oximes; Molecular Docking Simulation; Structure-Activity Relationship; Plant Weeds; Plant Proteins; Triazines; Esters; Molecular Structure; Ethers; Drug Discovery
PubMed: 38809794
DOI: 10.1021/acs.jafc.4c00272 -
Journal of Agricultural and Food... Jun 2024Myrosinase (Myr) catalyzes the hydrolysis of glucosinolates, yielding biologically active metabolites. In this study, glucoraphanin (GRA) extracted from broccoli seeds...
Myrosinase (Myr) catalyzes the hydrolysis of glucosinolates, yielding biologically active metabolites. In this study, glucoraphanin (GRA) extracted from broccoli seeds was effectively hydrolyzed using a Myr-obtained cabbage aphid () (Myr) to produce (R)-sulforaphane (SFN). The gene encoding Myr was successfully heterologously expressed in , resulting in the production of 1.6 g/L (R)-SFN, with a remarkable yield of 20.8 mg/g, achieved using recombination whole-cell catalysis under optimal conditions (pH 4.5, 45 °C). Subsequently, Myr underwent combinatorial simulation-driven mutagenesis, yielding a mutant, DE9 (N321D/Y426S), showing a remarkable 2.91-fold increase in the catalytic efficiency (/) compared with the original enzyme. Molecular dynamics simulations demonstrated that the N321D mutation in loopA of mutant DE9 enhanced loopA stability by inducing favorable alterations in hydrogen bonds, while the Y426S mutation in loopB decreased spatial resistance. This research lays a foundation for the environmentally sustainable enzymatic (R)-SFN synthesis.
Topics: Sulfoxides; Animals; Isothiocyanates; Aphids; Glycoside Hydrolases; Brassica; Insect Proteins; Glucosinolates; Kinetics; Molecular Dynamics Simulation; Oximes; Escherichia coli; Directed Molecular Evolution; Imidoesters
PubMed: 38809571
DOI: 10.1021/acs.jafc.4c02064