Search

[Display omitted] • The SAR profiles of 1,4-naphthoquinones for activating XO were first investigated. • Introduction of electron-donor/acceptor units in the A/B ring improved the effect. • The effect was well predicted using the HOMO-LUMO gap and the binding free energy. • The risk of 1,4-naphthoquinones was evaluated with kinetic data and in vivo exposure. Oral intake of 1,4-naphthoquinones could be a potential risk factor for hyperuricemia and gout via activation of xanthine oxidase (XO). Herein, 1,4-naphthoquinones derived from food and food-borne pollutants were selected to investigate the structure and activity relationship (SAR) and the relative mechanism for activating XO in liver S9 fractions from humans (HLS9) and rats (RLS9). The SAR analysis showed that introduction of electron-donating substituents on the benzene ring or electron-withdrawing substituents on the quinone ring improved the XO-activating effect of 1,4-naphthoquinones. Different activation potential and kinetics behaviors were observed for activating XO by 1,4-naphthoquinones in HLS9/RLS9. Molecular docking simulation and density functional theory calculations showed a good correlation between -LogEC 50 and docking free energy or HOMO-LUMO energy gap. The risk of exposure to the 1,4-naphthoquinones was evaluated and discussed. Our findings are helpful to guide diet management in clinic and avoid adverse events attributable to exposure to food-derived 1,4-naphthoquinones. [ABSTRACT FROM AUTHOR]

The differences in catalytic mechanism and domain between the soluble (S-COMT) and membrane-bound catechol- O -methyltransferase (MB-COMT) are poorly documented due to the unavailable crystal structure of MB-COMT. Considering the enzymatic nature of S-COMT and MB-COMT, the challenge could be solvable by probing the interactions between the enzymes with the ligands with minor differences in structures. Herein, isomeric shikonin and alkannin bearing a R/S -OH group in side chain at the C2 position were used for domain profiling of COMTs. Human and rat liver-derived COMTs showed the differences in inhibitory response (human's IC 50 and K i values for S-COMT < rat's, 5.80–19.56 vs. 19.56–37.47 μM; human's IC 50 and K i values for MB-COMT > rat's) and mechanism (uncompetition vs. noncompetition) towards the two isomers. The inhibition of the two isomers against human and rat S-COMTs was stronger than those for MB-COMTs (S-COMT's IC 50 and K i values < MB-COMT's, 5.80–37.47 vs. 40.01–111.8 μM). Additionally, the inhibition response of alkannin was higher than those of shikonin in no matter human and rat COMTs. Molecular docking stimulation was used for analysis. The inhibitory effects observed in in vitro and in silico tests were confirmed in vivo. These findings would facilitate further COMT-associated basic and applied research. [Display omitted] • The catalytic mechanism and domain of S-COMT and MB-COMT were probed using isomeric shikonin and alkannin. • S-COMT is more subject to inhibition by shikonin and alkannin compared with MB-COMT. • Alkannin has a higher inhibitory potency towards COMTs than that of shikonin. • The tendency mentioned above was investigated using inhibition kinetics and molecular docking, and further validated in vivo. • Species difference in inhibiting human and rat COMTs by shikonin and alkannin was studied and discussed mechanistically. [ABSTRACT FROM AUTHOR]

Polymeric carbon nitrides (CN), due to their unique physicochemical properties, versatile surface functionalization, ultra-high surface area, and good biocompatibility, have attracted considerable interest in diverse biomedical applications, such as biosensors, drug delivery, bioimaging, and theranostics. In this review, the recent advances in bioimaging of CN-based nanomaterials are summarized according to the imaging modalities, including optical (fluorescence and Raman) imaging, magnetic resonance imaging (MRI), photoacoustic imaging (PAI), computed tomography (CT), and multimodal imaging. The pros and cons of CN bioimaging are comprehensively analyzed and compared with those in previous reports. In the end, the prospects and challenges of their future bioimaging applications are outlooked. • Polymeric carbon nitride-based materials for bioimaging was reviewed. • Polymeric carbon nitride-based materials for optical imaging. • Polymeric carbon nitride-based materials for magnetic resonance imaging. • Polymeric carbon nitride-based materials for Computed tomography imaging. • Polymeric carbon nitride-based materials for Multimodal imaging. [ABSTRACT FROM AUTHOR]

Sepsis-Associated Liver Injury (SALI) is an independent risk factor for death from sepsis. The aim of this study was to develop an interpretable machine learning model for early prediction of 28-day mortality in patients with SALI. Data from the Medical Information Mart for Intensive Care (MIMIC-IV, v2.2, MIMIC-III, v1.4) were used in this study. The study cohort from MIMIC-IV was randomized to the training set (0.7) and the internal validation set (0.3), with MIMIC-III (2001 to 2008) as external validation. The features with more than 20% missing values were deleted and the remaining features were multiple interpolated. Lasso-CV that lasso linear model with iterative fitting along a regularization path in which the best model is selected by cross-validation was used to select important features for model development. Eight machine learning models including Random Forest (RF), Logistic Regression, Decision Tree, Extreme Gradient Boost (XGBoost), K Nearest Neighbor, Support Vector Machine, Generalized Linear Models in which the best model is selected by cross-validation (CV_glmnet), and Linear Discriminant Analysis (LDA) were developed. Shapley additive interpretation (SHAP) was used to improve the interpretability of the optimal model. At last, a total of 1043 patients were included, of whom 710 were from MIMIC-IV and 333 from MIMIC-III. Twenty-four clinically relevant parameters were selected for model construction. For the prediction of 28-day mortality of SALI in the internal validation set, the area under the curve (AUC (95% CI)) of RF was 0.79 (95% CI: 0.73–0.86), and which performed the best. Compared with the traditional disease severity scores including Oxford Acute Severity of Illness Score (OASIS), Sequential Organ Failure Assessment (SOFA), Simplified Acute Physiology Score II (SAPS II), Logistic Organ Dysfunction Score (LODS), Systemic Inflammatory Response Syndrome (SIRS), and Acute Physiology Score III (APS III), RF also had the best performance. SHAP analysis found that Urine output, Charlson Comorbidity Index (CCI), minimal Glasgow Coma Scale (GCS_min), blood urea nitrogen (BUN) and admission_age were the five most important features affecting RF model. Therefore, RF has good predictive ability for 28-day mortality prediction in SALI. Urine output, CCI, GCS_min, BUN and age at admission(admission_age) within 24 h after intensive care unit(ICU) admission contribute significantly to model prediction. [ABSTRACT FROM AUTHOR]

Sanguinarine (SAG) is the most abundant constituent of Macleaya cordata (Willd.) R. Br. (Popaceae). SAG has shown antimammary and colorectal metastatic effects in mice in vivo, suggesting its potential for cancer chemotherapy. To determine the antimetastatic effect and underlying molecular mechanisms of SAG on melanoma. CCK8 assay was used to determine the inhibition of SAG on the proliferation of A375 and A2058 cells. Network pharmacology analysis was applied to construct a compound-target network and select potential therapeutic targets of SAG against melanoma. Molecular docking simulation was conducted for further analysis of the selected targets. In vitro migration/invasion/western blot assay with 1, 1.5, 2 μM SAG and in vivo effect of 2, 4, 8 mg/kg SAG in xenotransplantation model in nude mice. The key targets of SAG treatment for melanoma were mainly enriched in PI3K-AKT pathway, and the binding energy of SAG to PI3K, AKT, and mTOR were −6.33, −6.31, and −6.07 kcal/mol, respectively. SAG treatment inhibited the proliferation, migration, and invasion ability of A375 and A2058 cells (p < 0.05) with IC50 values of 2.378 μM and 2.719 μM, respectively. It also decreased the phosphorylation levels of FAK, PI3K, AKT, mTOR and protein expression levels of MMP2 and ICAM-2. In the nude mouse xenograft model, 2, 4, 8 mg/kg SAG was shown to be effective in inhibiting tumour growth. Our research offered a theoretical foundation for the clinical antitumor properties of SAG, further suggesting its potential application in the clinic. [ABSTRACT FROM AUTHOR]

Pentagalloyl glucose (PGG) is a natural hydrolyzable gallotannin abundant in various plants and herbs. It has a broad range of biological activities, specifically anticancer activities, and numerous molecular targets. Despite multiple studies available on the pharmacological action of PGG, the molecular mechanisms underlying the anticancer effects of PGG are unclear. Here, we have critically reviewed the natural sources of PGG, its anticancer properties, and underlying mechanisms of action. We found that multiple natural sources of PGG are available, and the existing production technology is sufficient to produce large quantities of the required product. Three plants (or their parts) with maximum PGG content were Rhus chinensis Mill, Bouea macrophylla seed, and Mangifera indica kernel. PGG acts on multiple molecular targets and signaling pathways associated with the hallmarks of cancer to inhibit growth, angiogenesis, and metastasis of several cancers. Moreover, PGG can enhance the efficacy of chemotherapy and radiotherapy by modulating various cancer-associated pathways. Therefore, PGG can be used for treating different human cancers; nevertheless, the data on the pharmacokinetics and safety profile of PGG are limited, and further studies are essential to define the clinical use of PGG in cancer therapies. [ABSTRACT FROM AUTHOR]

During the past decade, the rapid construction of rail transit in developing countries has had a great impact on bus transport, resulting in the waste of public transport resources and ineffective competition between bus and rail transit. Therefore, it is particularly important to explore ways to promote the integrated development of bus and rail transit by combining both the effects of the built environment and their competition. Using Wuhan city in China as a case study, this study develops gradient boosting decision trees (GBDTs) to examine the quantified threshold range of the built environment impacts on bus transit trip rates and to further explore the competitive impacts of rail transit on bus transit within these threshold ranges. The threshold range results show that when the number of service point of interests (POIs) within a 500-m radius of the bus stop reaches 350 and the distance to the destination is 5 km, the model split of bus transit is the highest. The competition impact analysis shows that rail transit promotes bus transit trip rates in urban fringe areas and locations, including a high proportion of 3- to 5-km middle-distance trips, but restricts bus transit trip rates in high-density central areas and the regions dominated by short-distance trips of less than 3 km or long-distance trips of more than 5 km. Strategies are proposed to optimize land use and the layout of bus and rail transit stations to mitigate ineffective competition and improve the efficiency of public transit to provide theoretical and technical support for optimizing urban spatial layouts through transit-oriented development. [ABSTRACT FROM AUTHOR]

The eco–environmental toxicity of the rare metal palladium (Pd) has received extensive attention, thereby requiring simple and practical methods for detecting Pd. Herein, a new probe (HPD) based on dicyanoisophorone dye was designed and synthesized for the detection of Pd. HPD provides several advantages for tracking Pd, including near–infrared (NIR) emission (λ ex = 670 nm, λ em = 700 nm), naked–eye recognition, and comprehensive detection of 0/2/4 valence Pd with good selectivity and anti–interference. The reaction–sensing mechanism of HPD for Pd was further studied using density functional theory calculations. HPD was demonstrated to be a promising tool for the detection of Pd in real water samples, as well as the imaging of Pd in living cells and animals. [Display omitted] • A novel intramolecular charge transfer (ICT) based fluorescence probe was developed to detect palladium (Pd). • Near–infrared (NIR) emission and naked–eye detection of Pd are performed. • The detection mechanism of the probe was verified by experiments and calculations. • The probe can detect Pd in real water samples, living cells and animals. [ABSTRACT FROM AUTHOR]

Biothiols, including homocysteine (Hcy), cysteine (Cys) and reduced glutathione (GSH), play various roles in physiological and pathological processes. Because these biothiols possess similar in structures, it is difficult to discriminate Hcy, Cys and GSH from one another. In this work, a novel fluorescent probe, 4-BrCP , based on coumarin as a fluorophore to discriminate GSH from Hcy and Cys was rationally designed and synthesized in three steps with good total yield. The benzothiazol ring played the role of a fluorescent emission wavelength adjuster, while the ester part served as a fluorescent quencher and reactive sites with Hcy, Cys and GSH. The results of responsive experiment indicated that the probe could discriminate GSH from Hcy and Cys distinctly and exhibited a relatively high fluorescence quantum yield (0.84) and low detection limit (9.8 nM). In addition, the probe 4-BrCP also showed good stability and low toxicity. The reaction mechanism of 4-BrCP with GSH was speculated on according to the LC-MS data. Most importantly, because of the length of the skeletons of Hcy, Cys and GSH, different dynamic fluorescent phenomena were observed. Furthermore, imaging experiments suggested that the probe could be used to monitor GSH in living cells and organisms. [Display omitted] • A novel fluorescent probe based on coumarin was rationally designed and synthesized. • The probe could selectively discriminate GSH from Hcy, Cys, or Hcy/Cys/GSH coexisting condition. • The probe showed a good quantum yield (0.84) and low detection limit (9.8 nM). • The probe could trace endogenous GSH in living cells and organisms. [ABSTRACT FROM AUTHOR]

Since smallpox was eradicated in 1980, the monkeypox virus (MPXV) has emerged as the most threatening orthopoxvirus in the world. In this study, we conducted a comprehensive analysis of the currently published complete genome sequences of the monkeypox virus. The core/variable regions were identified through core-pan analysis of MPXV. Besides single-nucleotide polymorphisms, our study also revealed that specific genes, multi-copy genes, repeat sequences, and recombination fragments are primarily distributed in the variable region. This result suggests that variable regions are not only more susceptible to single-base mutations, but also to events such as gene loss or gain, as well as recombination. Taken together, our results demonstrate the genomic characteristics of the core/variable regions of MPXV, and contribute to our understanding of the evolution of MPXV. • Our study found that specific genes, multi-copy genes, repeat sequences and recombination fragments are mostly distributed in the variable region. • Our results demonstrate genomic characteristics of core/variable regions of the mpxv. [ABSTRACT FROM AUTHOR]

This study aimed to develop a novel and practical fluorescent method for GSH detection in complex biological samples. To this end, a series of coumarin-based fluorescent probes was designed and synthesized using various aliphatic halogens as the sensing group. By using a new evaluation method of GSH/Cys/Hcy coexisting conditions, the probe with chloropropionate (CBF3) showed a high selectivity, excellent sensitivity, good stability for GSH detection. The reaction mechanism is proposed as nucleophilic substitution/cyclization and intramolecular charge transfer (ICT), which was confirmed by LC-MS and NMR analysis, as well as density functional theory calculations. In addition, CBF3 was demonstrated to be competent not only for the quantitative detection of GSH in real serum samples, but also for sensing GSH changes in different oxidative stress models in living cells and nematodes. This study showed a practical strategy for constructing GSH-specific fluorescent probes, and provided a sensitive tool for real-time sensing of GSH in real biological samples. The findings would greatly facilitate further investigations on GSH-associated clinical diagnosis and biomedical studies. Image 1 • A novel SN 2 -triggered and ICT-based fluorescent probe was developed for sensing GSH. • The reaction mechanism was confirmed by experimental and theoretical investigations. • The probe selectively responded to GSH in the GSH/Cys/Hcy coexisting conditions. • The probe exhibited a low detection limit of 9.2 nM. • The probe could monitor GSH in real serum sample, and in living cells and nematodes. [ABSTRACT FROM AUTHOR]

In this study, an imidazole-coumarin based fluorescent probe was developed for the selective and sensitive detection of Ag+ in aqueous solution. Using a combination of Job plot, NMR titrations, and DFT calculations, the binding properties between Ag+ and the probe were deeply investigated, and the results revealed a 1:1 binding stoichiometry between the probe and Ag+ with a binding constant of 1.02 × 106 M−1. The detection limit was found to be 150 nM, which satisfies the requirement for the quantitative detection of Ag+ in real water samples. Moreover, the new probe, Ic, was successfully applied to sense Ag+ in HeLa and HepG2 cells as well as in C. elegans, indicating that it could be a useful tool for the environmental monitoring of Ag+ pollution. These results demonstrated that Ic could serve as a high-efficiency and low-cost fluorescent probe for tracking Ag+ in an aquatic environment and biological organisms. [ABSTRACT FROM AUTHOR]

Numerous types of molecular mechanisms mediate the development of cancer. Non-coding RNAs (ncRNAs) are being increasingly recognized to play important role in mediating the development of diseases, including cancer. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are the two most widely studied ncRNAs. Thus far, lncRNAs are known to have biological roles through a variety of mechanisms, including genetic imprinting, chromatin remodeling, cell cycle control, splicing regulation, mRNA decay and translational regulation, and miRNAs regulate gene expression through the degradation of mRNAs and lncRNAs. Although ncRNAs account for a major proportion of the total RNA, the mechanisms underlying the physiological or pathological processes mediated by various types of ncRNAs, and the specific interaction mechanisms between miRNAs and lncRNAs in various physiological and pathological processes, remain largely unknown. Thus, further research in this field is required. In general, the interaction mechanisms between miRNAs and lncRNAs in human cancer have become important research topics, and the study thereof has led to the recent development of related technologies. By providing examples and descriptions, and performing chart analysis, the present study aimed to review the interaction mechanisms and research approaches for these two types of ncRNAs, as well as their roles in the occurrence and development of cancer. These details have far-reaching significance for the utilization of these molecules in the diagnosis and treatment of cancer. [ABSTRACT FROM AUTHOR]

Improving the detection reliability of biosensors is essential but challenging. The dual-signal self-checking function is useful for the development of reliable biosensors; however, it inevitably increases the complexity of the sensing system. Thus, biosensors with intrinsic self-checking functions that do not require additional chemicals, specific sensor assemblies, and/or instruments are highly desirable. Herein, integrating the ability of fluorescence detection and photodegradation by carbon nitride nanosheets (CNNS), a biosensor with a self-checking function for sensitive telomerase activity detection was constructed. Acriflavine (AF) was screened from various dyes to form the most effective CNNS-AF donor-acceptor (D-A) interfaces by experiments and density functional theory (DFT) calculations, considering spectral match, electrostatic interaction, and non-covalent stacking. As a result, the proposed fluorescence biosensor not only showed highly sensitive detection of telomerase activity but also had an internal self-checking function by photodegradation of AF via continuous excitation and measurement of recovered fluorescence. This study sheds light on CNNS-based D-A interfaces with synergistic fluorescence detection and photocatalysis-induced self-checking properties for future clinical diagnosis with high sensitivity and reliability. • A biosensor with an intrinsic self-checking function for sensitive telomerase activity detection was constructed. • The self-checking function did not require additional chemicals, specific sensor assemblies, and/or instruments. • Carbon nitride-acriflavine was selected as the most effective donor-acceptor pair by experiments and DFT calculations. • Donor-acceptor fluorescent sensing and photocatalyst-based self-checking was coupled using carbon nitrides of multi-roles. [ABSTRACT FROM AUTHOR]

Abstract 1. Human exposure to magnolol can reach a high dose in daily life. Our previous studies indicated that magnolol showed high affinities to several UDP-glucuronosyltransferases (UGTs) This study was designed to examine the in vitro inhibitory effects of magnolol on UGTs, and further to evaluate the possibility of the in vivo inhibition that might happen. 2. Assays with recombinant UGTs and human liver microsomes (HLM) indicated that magnolol (10 μM) can selectively inhibit activities of UGT1A9 and extra-hepatic UGT1A7. Inhibition of magnolol on UGT1A7 followed competitive inhibition mechanism, while the inhibition on UGT1A9 obeyed either competitive or mixed inhibition mechanism, depending on substrates. The Ki values for UGT1A7 and 1A9 are all in nanomolar ranges, lower than possible magnolol concentrations in human gut lumen and blood, indicating the in vivo inhibition on these two enzymes would likely occur. 3. In conclusion, UGT1A7 and 1A9 can be strongly inhibited by magnolol, raising the alarm for safe application of magnolol and traditional Chinese medicines containing magnolol. Additionally, given that UGT1A7 is an extrahepatic enzyme, magnolol can serve as a selective UGT1A9 inhibitor that will act as a new useful tool in future hepatic glucuronidation phenotyping. [ABSTRACT FROM AUTHOR]

A novel two-photon pH probe, 3-benzimidazole-7-hydroxycoumarin (BHC), was designed and synthesized based on the structures of hydroxycoumarin and benzimidazole. BHC showed good linearity in the pH ranges of 3.30–5.40 (pKa = 4.20) and 6.50–8.30 (pKa = 7.20) at a maximum emission wavelength of 480 nm. BHC in acidic and alkaline media could be distinguished by an obvious spectral shift of the maximum absorption wavelength from 390 nm to 420 nm. In addition, BHC was well localized to mitochondria and successfully applied to one-photon and two-photon imaging of pH changes in the mitochondria of HeLa cells. The findings presented herein suggest that BHC can serve as an excellent fluorescent probe for selectively sensing mitochondrial pH changes with remarkable photostability and low cytotoxicity. Unlabelled Image • A new fluorescent probe for one- and two-photon sensing of pH was developed. • The probe responded sensitively and selectively to pH changes within 3.0–6.0 (pKa = 4.20) and 6.0–9.0 (pKa = 7.20). • The probe was successfully applied for monitoring and imaging of mitochondrial pH in living cells. [ABSTRACT FROM AUTHOR]

Compared with coumarin, 7-hydroxycoumarin could serve as a better hit for developing CYP2A6 inhibitors. In this study, a series of 7-hydroxycoumarin and its structural analogues were collected to study their structure-activity relationship (SAR) and isoform selectivity for inhibiting CYP2A6. All tested coumarins except a C4 phenyl derivative (11) showed higher inhibitory activities for CYP2A6 over the other CYP isoforms, including CYP1A2, CYP2D6, CYP2E1, CYP3A4, CYP2C8, and CYP2C9. Of these coumarins, 6,7-dihydroxycoumarin (1) and 7,8-dihydroxycoumarin (9) were found to be potent inhibitors of CYP2A6 with IC 50 / K i value of 0.39/0.25 and 4.61/3.02 μM, respectively, compared to methoxalen as positive control (IC 50 / K i = 0.43/0.26 μM). In contrast, other coumarins showed low or decreased CYP2A6-inhibiting activities. SAR analysis showed that hydroxy groups might be important for CYP2A6 inhibition, and the rank order of sites for hydroxy substitution was C6 > C7 > C8. In addition, either hydrophobic or hydrophilic substituents introduced into C4, C6 and C8 led to a reduction in CYP2A6-inhibiting activity, and the degree of influence was dependent on the size and electrical charge of substituents. Furthermore, inhibition kinetic analysis and docking simulations demonstrated that the 8- O -glucosylated coumarin derivative (17) exhibited noncompetitive inhibition against CYP2A6, while competitive inhibition patterns were noted for the other tested coumarins. The mechanisms underlying the inhibitors binding to CYP2A6 were further investigated by molecular docking study. The findings presented herein are very helpful for developing highly selective and more potent CYP2A6 inhibitors. Unlabelled Image [ABSTRACT FROM AUTHOR]