Abstract
Background
The study of drug–target interactions (DTIs) affinity plays an important role in safety assessment and pharmacology. Currently, quantitative structure–activity relationship (QSAR) ...and molecular docking (MD) are most common methods in research of DTIs affinity. However, they often built for a specific target or several targets, and most QSAR and MD methods were based either on structure of drug molecules or on structure of receptors with low accuracy and small scope of application. How to construct quantitative prediction models with high accuracy and wide applicability remains a challenge. To this end, this paper screened molecular descriptors based on molecular vibrations and took molecule-target as a whole system to construct prediction models with high accuracy-wide applicability based on dissociation constant (Kd) and concentration for 50% of maximal effect (EC50), and to provide reference for quantifying affinity of DTIs.
Results
After comprehensive comparison, the results showed that RF models are optimal models to analyze and predict DTIs affinity with coefficients of determination (R
2
) are all greater than 0.94. Compared to the quantitative models reported in literatures, the RF models developed in this paper have higher accuracy and wide applicability. In addition, E-state molecular descriptors associated with molecular vibrations and normalized Moreau-Broto autocorrelation (G3), Moran autocorrelation (G4), transition-distribution (G7) protein descriptors are of higher importance in the quantification of DTIs.
Conclusion
Through screening molecular descriptors based on molecular vibrations and taking molecule-target as whole system, we obtained optimal models based on RF with more accurate-widely applicable, which indicated that selection of molecular descriptors associated with molecular vibrations and the use of molecular-target as whole system are reliable methods for improving performance of models. It can provide reference for quantifying affinity of DTIs.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The adjustment of metabolic patterns is fundamental to fungal biology and plays vital roles in adaptation to diverse ecological challenges. Nematode-trapping fungi can switch their lifestyle from ...saprophytic to pathogenic by developing specific trapping devices induced by nematodes to infect their prey as a response to nutrient depletion in nature. However, the chemical identity of the specific fungal metabolites used during the switch remains poorly understood. We hypothesized that these important signal molecules might be volatile in nature. Gas chromatography-mass spectrometry was used to carry out comparative analysis of fungal metabolomics during the saprophytic and pathogenic lifestyles of the model species
Two media commonly used in research on this species, cornmeal agar (CMA) and potato dextrose agar (PDA), were chosen for use in this study. The fungus produced a small group of volatile furanone and pyrone metabolites that were associated with the switch from the saprophytic to the pathogenic stage.
fungi grown on CMA tended to produce more traps and employ attractive furanones to improve the utilization of traps, while fungi grown on PDA developed fewer traps and used nematode-toxic furanone metabolites to compensate for insufficient traps. Another volatile pyrone metabolite, maltol, was identified as a morphological regulator for enhancing trap formation. Deletion of the gene
in
led to increased amounts of the furanone attractant (2-fold) in mutants and enhanced the attractive activity (1.5-fold) of the fungus, while it resulted in decreased trap formation. This investigation provides new insights regarding the comprehensive tactics of fungal adaptation to environmental stress, integrating both morphological and metabolomic mechanisms.
Nematode-trapping fungi are a unique group of soil-living fungi that can switch from the saprophytic to the pathogenic lifestyle once they come into contact with nematodes as a response to nutrient depletion. In this study, we investigated the metabolic response during the switch and the key types of metabolites involved in the interaction between fungi and nematodes. Our findings indicate that
develops multiple and flexible metabolic tactics corresponding to different morphological responses to nematodes.
can use similar volatile furanone and pyrone metabolites with different ecological functions to help capture nematodes in the fungal switch from the saprophytic to the pathogenic lifestyle. Furthermore, studies with
mutants with increased furanone and pyrone metabolites confirmed the results. This investigation reveals the importance of volatile signaling in the comprehensive tactics used by nematode-trapping fungi, integrating both morphological and metabolomic mechanisms.
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•Experiments show that the natural component 3-hydroxymorindone in the traditional Chinese medicine Knoxia roxburghii (Spreng.) M. A. Rau induces ROS-mediated mitochondrial ...dysfunction cervical cancer cell apoptosis.•To explore the mechanism of 3-hydroxymorindone anti-cervical cancer by network pharmacology, molecular docking and western blotting.•Provide a potential natural compound for treating cervical cancer.
Knoxia roxburghii (Spreng.) M. A. Rau (KR) is used in Chinese traditional medicine with potential anti-cancer effects. Previous studies have shown that anthraquinone component 3-hydroxymorindone (3-H) isolated from KR has a strong cytotoxic effect on tumor cells, but its molecular mechanism has not been studied yet. The cytotoxicity of 3-H to different tumor cells has been demonstrated in the present study. Network pharmacology and molecular biology techniques were used to explore the possible mechanism of cervical cancer cells (HeLa, SiHa, and C33A cells) with the most significant toxicity. 3-H inhibited the proliferation and migration of cervical cancer cells, triggered ROS accumulation, reduced mitochondrial membrane potential (ΔΨM), and cell apoptosis. Western blotting analysis showed that it could induce HeLa cells apoptosis by down-regulating the PI3K/AKT/NF-κB signaling pathway. Moreover, ROS inhibitor inhibited 3-H-induced cell proliferation and PI3K inhibitor synergized 3-H-induced cell proliferation inhibition. As well as, the inhibition of p-PI3K, p-Akt, and p-NF-κB by 3-H could be compensated by the ROS inhibitor. Taken together, these results suggest that 3-H induces apoptosis of human cervical cancer cells by up-regulating ROS-mediated mitochondrial dysfunction and down-regulating PI3K/AKT/NF-κB signaling pathways. The result of this research provides a promising potential compound for the development of anti-cervical cancer drugs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mitogen-activated protein kinase (MAPK) cascades are broadly conserved and play essential roles in multiple cellular processes, including fungal development, pathogenicity, and secondary metabolism. ...Their function, however, also exhibits species and strain specificity.
Penicillium oxalicum
secretes plant-biomass-degrading enzymes (PBDEs) that contribute to the carbon cycle in the natural environment and to utilization of lignocellulose in industrial processes. However, knowledge of the MAPK pathway in
P. oxalicum
has been relatively limited. In this study, comparative transcriptomic analysis of
P. oxalicum
, cultured on different carbon sources, found ten putative kinase genes with significantly modified transcriptional levels. Six of these putative kinase genes were knocked out in the parental strain ∆
PoxKu70
, and deletion of the gene,
Fus3
/
Kss1
-like
PoxMK1
(
POX00158
), resulted in the largest reduction (91.1%) in filter paper cellulase production. Further tests revealed that the mutant ∆
PoxMK1
lost 37.1 to 92.2% of PBDE production, under both submerged- and solid-state fermentation conditions, compared with ∆
PoxKu70
. In addition, the mutant ∆
PoxMK1
had reduced vegetative growth and increased pigment biosynthesis. Comparative transcriptomic analysis showed that
PoxMK1
deletion from
P. oxalicum
downregulated the expression of major PBDE genes and known regulatory genes such as
PoxClrB
and
PoxCxrB
, whereas the transcription of pigment biosynthesis-related genes was upregulated. Comparative phosphoproteomic analysis revealed that
PoxMK1
deletion considerably modified phosphorylation of key transcription- and signal transduction-associated proteins, including transcription factors Mcm1 and Atf1, RNA polymerase II subunits Rpb1 and Rpb9, MAPK-associated Hog1 and Ste7, and cyclin-dependent kinase Kin28. These findings provide novel insights into understanding signal transduction and regulation of PBDE gene expression in fungi.
Key points
• PoxMK1 is involved in expression of PBDE- and pigment synthesis-related genes.
• PoxMK1 is required for vegetative growth of P. oxalicum.
• PoxMK1 is involved in phosphorylation of key TFs, kinases, and RNA polymerase II.
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CEKLJ, DOBA, EMUNI, FZAB, GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Using information technology to extract emergency decision-making knowledge from emergency plan documents is an essential means to enhance the efficiency and capacity of emergency management. To ...address the problems of numerous terminologies and complex relationships faced by emergency knowledge extraction of water diversion project, a multi-feature graph convolutional network (PTM-MFGCN) based on pre-trained model is proposed. Initially, through the utilization of random masking of domain-specific terminologies during pre-training, the model's comprehension of the meaning and application of such terminologies within specific fields is enhanced, thereby augmenting the network's proficiency in extracting professional terminologies. Furthermore, by introducing a multi-feature adjacency matrix to capture a broader range of neighboring node information, thereby enhancing the network's ability to handle complex relationships. Lastly, we utilize the PTM-MFGCN to achieve the extraction of emergency entity relationships in water diversion project, thus constructing a knowledge graph for water diversion emergency management. The experimental results demonstrate that PTM-MFGCN exhibits improvements of 2.84% in accuracy, 4.87% in recall, and 5.18% in F1 score, compared to the baseline model. Relevant studies can effectively enhance the efficiency and capability of emergency management, mitigating the impact of unforeseen events on engineering safety.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The development of stimuli‐responsive circularly polarized luminescence (CPL) materials is quite attractive but challenging. Here, a pair of atomically precise enantiomers R/S‐Ag20 nanoclusters has ...been synthesized using chiral acid ligands. And then, stimuli‐responsive CPL materials were developed by assembling the chiral silver nanoclusters with an achiral bridging ligand. The atomically precise silver cluster‐assembled materials produce CPL with a dissymmetry factor (|glum|) of 1 × 10−3, through the high‐efficiency chiral induction process. More interestingly, the single CPL band at room temperature could quickly transform into highly separated dual CPL emissions at low temperature. This study provides a new strategy for the rational functionalization of chiral silver clusters in preparing cluster‐based CPL emitters and enriches the types of stimuli‐responsive CPL materials.
The temperature‐triggered dynamic circularly polarized luminescence materials were constructed by the coordination assembly of chiral silver nanoclusters and luminophor linkers.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Irinotecan (IRI) chemotherapy toxicities can be severe, and may result in treatment delay, morbidity and in some rare cases death. Neutropenia is a life-threatening side effect of irinotecan, and UDP ...glucuronosyltransferases (UGTs) gene polymorphisms could predict the side effects in cancer patients and then reduce IRI-induced toxicity by preventative treatment or a decrease in dose. Both UGT1A1*6 and *28 were reliably demonstrated to be risk factors for IRI-induced neutropenia, with tests for both polymorphisms potentially being particularly useful in Asian cancer patients. However, some researchers reported that UGT1A1*6 could predict IRI-induced toxicities in Asian populations, controversial conclusions still remained. Thus, the association between UGT1A1*6 polymorphisms and IRI-induced severe toxicity in cancer patients is still needed to be explored. Therefore, this study aims to investigate the association between UGT1A1*6 polymorphisms and IRI-related severe neutropenia in cancer patients on a large scale. A total of 12 studies that included 746 wild genotype (G/G) cases and 394 variant genotype (G/A and A/A) cases were included on the basis of inclusion criteria. Then we assessed the methodologies quality; odds ratio (OR), risk difference (RD) and 95% confidence intervals (95% CI) were used to assess the strength of association. Overall, an increased risk of severe neutropenia in cancer patients with UGT1A1*6 polymorphisms was found. Patients with recessive models (GA + AA vs. GG) of UGT1A1*6 showed an increased risk (OR 2.03, 95% CI 1.54–2.68; RD = 0.11,
P
< 0.001). Specifically, the heterozygous variant of UGT1A1*6 showed an increased risk (OR 1.83, 95% CI 1.36–2.46; RD = 0.09,
P
< 0.001), and homozygous mutation showed also high risk (OR 2.95, 95% CI 1.83–4.75; RD = 0.18,
P
< 0.001) for severe neutropenia. Subgroup meta-analysis revealed that for patients harboring both heterozygous and homozygous variants, cancer types, low dose of IRI and the duration of treatment also presented comparably increased risk in suffering severe neutropenia. As for country, in China and Japan, there was a statistically increased severe neutropenia with variant genotype of UGT1A1*6 (China: GA + AA vs. GG, OR 1.83, 95% CI 1.28–2.59; RD = 0.08,
P
= 0.001; Japan: GA + AA vs. GG, OR 2.39, 95% CI 1.45–3.92; RD = 0.15,
P
= 0.001). In conclusion, in this meta-analysis, the UGT1A1*6 polymorphisms were associated with an increased risk of IRI-induced neutropenia in cancer patients, and increased incidences of severe neutropenia could be correlated with diverse regions, cancer type, low dose of IRI and the duration of treatment.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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A novel series of compounds obtained by fusing the acetylcholinesterase (AChE) inhibitor donepezil and the antioxidant melatonin were designed as multi-target-directed ligands for the ...treatment of Alzheimer’s disease (AD). In vitro assay indicated that most of the target compounds exhibited a significant ability to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (eqBuChE and hBuChE), and β-amyloid (Aβ) aggregation, and to act as potential antioxidants and biometal chelators. Especially, 4u displayed a good inhibition of AChE (IC50 value of 193nM for eeAChE and 273nM for hAChE), strong inhibition of BuChE (IC50 value of 73nM for eqBuChE and 56nM for hBuChE), moderate inhibition of Aβ aggregation (56.3% at 20μM) and good antioxidant activity (3.28trolox equivalent by ORAC assay). Molecular modeling studies in combination with kinetic analysis revealed that 4u was a mixed-type inhibitor, binding simultaneously to catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4u could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood–brain barrier (BBB). Taken together, these results strongly indicated the hybridization approach is an efficient strategy to identify novel scaffolds with desired bioactivities, and further optimization of 4u may be helpful to develop more potent lead compound for AD treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
As an analog of clopidogrel and prasugrel, vicagrel is completely hydrolyzed to intermediate thiolactone metabolite 2‐oxo‐clopidogrel (also the precursor of active thiol metabolite H4) in human ...intestine, predominantly by AADAC and CES2; however, other unknown vicagrel hydrolases remain to be identified. In this study, recombinant human Raf kinase inhibitor protein (rhRKIP) and pooled human intestinal S9 (HIS9) fractions and microsome (HIM) preparations were used as the different enzyme sources; prasugrel as a probe drug for RKIP (a positive control), vicagrel as a substrate drug of interest, and the rate of the formation of thiolactone metabolites 2‐oxo‐clopidogrel and R95913 as metrics of hydrolase activity examined, respectively. In addition, an IC50 value of inhibition of rhRKIP‐catalyzed vicagrel hydrolysis by locostatin was measured, and five classical esterase inhibitors with distinct esterase selectivity were used to dissect the involvement of multiple hydrolases in vicagrel hydrolysis. The results showed that rhRKIP hydrolyzed vicagrel in vitro, with the values of Km, Vmax, and CLint measured as 20.04 ± 1.99 μM, 434.60 ± 12.46 nM/min/mg protein, and 21.69 ± 0.28 ml/min/mg protein, respectively, and that an IC50 value of locostatin was estimated as 1.24 ± 0.04 mM for rhRKIP. In addition to locostatin, eserine and vinblastine strongly suppressed vicagrel hydrolysis in HIM. It is concluded that RKIP can catalyze the hydrolysis of vicagrel in the human intestine, and that vicagrel can be hydrolyzed by multiple hydrolases, such as RKIP, AADAC, and CES2, concomitantly.
As a promising novel antiplatelet drug and an analog of clopidogrel and prasugrel, vicagrel is hydrolyzed to its thiolactone metabolite 2‐oxo‐clopidogrel by esterases AADAC and CES2 in human intestine. In this study, vicagrel was hydrolyzed to 2‐oxo‐clopidogrel by RKIP (Raf kinase inhibitor protein) as measured with recombinant human RKIP and human intestine S9 and microsome preparations, respectively, showing that vicagrel is the second substrate drug of RKIP in humans, next to prasugrel.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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