Discovery of an EP300 Inhibitor using Structure-based Virtual Screening and Bioactivity Evaluation.

BACKGROUND: EP300 (E1A binding protein p300) played a significant role in serial diseases such as cancer, neurodegenerative disease. Therefore, it became a significant target. METHODS: Targeting EP300 discovery of a novel drug to alleviate these diseases. In this paper, 17 candidate compounds were obtained using a structure-based virtual screening approach, 4449-0460, with an IC50 of 5.89 ± 2.08 uM, which was identified by the EP300 bioactivity test. 4449-0460 consisted of three rings. The middle benzene ring connected the 5-ethylideneimidazolidine-2,4-dione group and the 3-F-Phenylmethoxy group. RESULTS: Furthermore, the interaction mechanism between 4449-0460 and EP300 was explored by combining molecular dynamics (MD) simulations and binding free energy calculation methods. CONCLUSION: The binding free energy of EP300 with 4449-0460 was -10.93 kcal/mol, and mainly came from the nonpolar energy term (ΔGnonpolar). Pro1074, Phe1075, Val1079, Leu1084, and Val1138 were the key residues in EP300/4449-0460 binding with more -1 kcal/mol energy contribution. 4449-0460 was a promising inhibitor targeting EP300, which had implications for the development of drugs for EP300-related diseases.

Elucidation of the anti-gastric cancer mechanism of Guiqi Baizhu Formula by integrative approach of chemical bioinformatics.

Gastric cancer (GC) has posed a great threat to the lives of people around the world. To date, safer and more cost-effective therapy for GC is lacking. Traditional Chinese medicine (TCM) may provide some new options for this. Guiqi Baizhu Formula (GQBZF), a classic TCM formula, has been extensively used to treat GC, while its bioactive components and therapeutic mechanisms remain unclear. In this study, we evaluated the underlying mechanisms of GQBZF in treating GC by integrative approach of chemical bioinformatics. GQBZF lyophilized powder (0.0625 mg/mL, 0.125 mg/mL) significantly attenuated the expression of p-IGF1R, PI3K, p-PDK1, p-VEGFR2 to inhibit the proliferation, migration and induce apoptosis of gastric cancer cells, which was consistent with the network pharmacology. Additionally, atractylenolide Ⅰ, quercetin, glycyrol, physcione and aloe-emodin, emodin, kaempferol, licoflavone A were found to be the key compounds of GQBZF regulating IGF1R and VEGFR2, respectively. And among which, glycyrol and emodin were determined as key active compounds against GC by farther vitro experiments and LC/MS. Meanwhile, we also found that glycyrol inhibited MKN-45 cells proliferation and enhanced apoptosis, which might be related to the inhibition of IGF1R/PI3K/PDK1, and emodin could significantly attenuate the MKN-45 cells migration, which might be related to the inhibition of VEGFR2-related signaling pathway. These results were verified again by molecular dynamics simulation and binding interaction pattern. In summary, this study suggested that GQBZF and its key active components (glycyrol and emodin) can suppress IGF1R/PI3K/PDK1 and VEGFR2-related signaling pathway, thereby inhibiting tumor cell proliferation and migration and inducing apoptosis. These findings provided an important strategy for developing new agents and facilitated clinical use of GQBZF against GC.

DTNPD: A comprehensive database of drugs and targets for neurological and psychiatric disorders.

In response to the shortcomings in data quality and coverage for neurological and psychiatric disorders (NPDs) in existing comprehensive databases, this paper introduces the DTNPD database, specifically designed for NPDs. DTNPD contains detailed information on 30 NPDs types, 1847 drugs, 514 drug targets, 64 drug combinations, and 61 potential target combinations, forming a network with 2389 drug-target associations. The database is user-friendly, offering open access and downloadable data, which is crucial for network pharmacology studies. The key strength of DTNPD lies in its robust networks of drug and target combinations, as well as drug-target networks, facilitating research and development in the field of NPDs. The development of the DTNPD database marks a significant milestone in understanding and treating NPDs. For accessing the DTNPD database, the primary URL is http://dtnpd.cnsdrug.com, complemented by a mirror site available at http://dtnpd.lyhbio.com.

Influence of microplastics on the availability of antibiotics in soils.

Microplastics (MPs) and antibiotics, as two major types of emerging pollutants, inevitably coexist in the soil environment due to agricultural film residue, sewage irrigation and sludge application. However, the impact of MPs on antibiotic availability in soils with varying characteristics has not been extensively studied. Therefore, in this study, an interference experiment was conducted using three types of MPs (polyethylene (PE), polyvinyl chloride (PVC) and polypropylene (PP)) in red soil, paddy soil and cinnamon soil. The available antibiotics in soils were evaluated using diffusive gradients in thin-films (DGT). Results showed that MPs had a significant impact on the amount of antibiotics adsorbed on soil solid (Cs) by providing additional binding sites or altering soil characteristics (e.g., pH and dissolved organic carbon). The most significant effects on Cs were observed in cinnamon soil, and the Cs values were dependent on concentration of MPs. The available antibiotics, as measured by DGT significantly decreased after the addition of MPs. This decrease was influenced by the soil characteristics. However, the concentration of antibiotics in soil solutions (Cd) was only slightly impacted by MPs. Therefore, the influence of MPs on the migration of antibiotics was reflected by their impact on the soil/water partition coefficient (Kd), while the resupply ability (R) from the soil solid phase was less influential. Moreover, the dosage of MPs had a significant effect on the availability of antibiotics in CS by promoting the adsorption of antibiotics on the solid phase, while in RS and PS, the soil properties played a dominate role in the changes in antibiotic availability after MP addition. These results indicate that the impact of MPs on available antibiotics mainly depends on soil properties. In addition, DGT measurement is more sensitive than soil solution to investigate the effects of coexisting pollutants on the behavior of antibiotics in soil.

Retracted: Resveratrol Suppresses Human Nasopharyngeal Carcinoma Cell Growth Via Inhibiting Differentiation Antagonizing Non-Protein Coding RNA (DANCR) Expression.

The authors have requested retraction due to the identification of errors in the data. Reference: Jiafeng Zhang, Xiaojie Jin, Chuan Zhou, Hui Zhao, Ping He, Yalin Hao, Qiongna Dong. Resveratrol Suppresses Human Nasopharyngeal Carcinoma Cell Growth Via Inhibiting Differentiation Antagonizing Non-Protein Coding RNA (DANCR) Expression. Med Sci Monit, 2020; 26: e923622. DOI: 10.12659/MSM.923622.

Structure-Based Discovery of the SARS-CoV-2 Main Protease Noncovalent Inhibitors from Traditional Chinese Medicine.

Traditional Chinese medicine (TCM) has been extensively employed for the treatment of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there is demand for discovering more SARS-CoV-2 Mpro inhibitors with diverse scaffolds to optimize anti-SARS-CoV-2 lead compounds. In this study, comprehensive in silico and in vitro assays were utilized to determine the potential inhibitors from TCM compounds against SARS-CoV-2 Mpro, which is an important therapeutic target for SARS-CoV-2. The ensemble docking analysis of 18263 TCM compounds against 15 SARS-CoV-2 Mpro conformations identified 19 TCM compounds as promising candidates. Further in vitro testing validated three compounds as inhibitors of SARS-CoV-2 Mpro and showed IC50 values of 4.64 ± 0.11, 7.56 ± 0.78, and 11.16 ± 0.26 µM, with EC50 values of 12.25 ± 1.68, 15.58 ± 0.77, and 29.32 ± 1.25 µM, respectively. Molecular dynamics (MD) simulations indicated that the three complexes remained stable over the last 100 ns of production run. An analysis of the binding mode revealed that the active compounds occupy different subsites (S1, S2, S3, and S4) of the active site of SARS-CoV-2 Mpro via specific poses through noncovalent interactions with key amino acids (e.g., HIS 41, ASN 142, GLY 143, MET 165, GLU 166, or GLN 189). Overall, this study provides evidence indicating that the three natural products obtained from TCM could be further used for anti-COVID-19 research, justifying the investigation of Chinese herbal medicinal ingredients as bioactive constituents for therapeutic targets.

Prediabetes and the incidence of Parkinson's disease: A meta-analysis.

Diabetes has been associated with an elevated risk of Parkinson's disease (PD), yet the relationship between prediabetes (PreD) and the incidence of PD in the adult population remains unclear. Therefore, a systematic review and meta-analysis was conducted to evaluate if PreD is also associated with a higher risk of PD. We conducted comprehensive searches of the PubMed, Embase, and Web of Science databases to identify relevant observational studies with longitudinal follow-up. The random-effects model was employed to synthesize the data, mitigating the potential impact of study heterogeneity on the outcomes. Our analysis incorporated seven datasets from five cohort studies, encompassing 18,170,592 adult participants without a PD diagnosis at baseline. Among them, 2,432,148 (13.3%) had PreD. During the follow-up, a total of 46,682 patients were diagnosed with PD. The pooled results indicated that PreD was associated with an increased incidence of PD (risk ratio [RR] 1.09, 95% confidence interval [CI] 1.02 - 1.16; P = 0.02; I2 = 52%), after adjusting for potential confounding factors such as age, sex, body mass index (BMI), and smoking. Subsequent pilot subgroup analyses suggested that the association between PreD and PD might not be significantly influenced by the country of the study, its design, age or sex of the participants, definition of PreD, or the quality scores of the study (P for subgroup difference all > 0.05). In conclusion, adult population with PreD may have a mildly increased risk of developing PD compared to those with normoglycemia.

Brønsted Acid-Catalyzed Intramolecular Tandem Double Cyclization of γ-Hydroxy Acetylenic Ketones with Alkynes into Naphtho[1,2-b]furan-3-ones.

A metal-free and atom-economic route for the synthesis of naphtho[1,2-b]furan-3-ones has been realized via p-TsOH·H2O-catalyzed intramolecular tandem double cyclization of γ-hydroxy acetylenic ketones with alkynes in formic acid. The benzene-linked furanonyl-ynes are the key intermediates obtained by the scission/recombination of C-O double bonds. Further, the structural modifications of the representative product were implemented by reduction, demethylation, substitution, and [5 + 2]-cycloaddition.

Contrastive Masked Autoencoders are Stronger Vision Learners.

Masked image modeling (MIM) has achieved promising results on various vision tasks. However, the limited discriminability of learned representation manifests there is still plenty to go for making a stronger vision learner. Towards this goal, we propose Contrastive Masked Autoencoders (CMAE), a new self-supervised pre-training method for learning more comprehensive and capable vision representations. By elaboratively unifying contrastive learning (CL) and masked image model (MIM) through novel designs, CMAE leverages their respective advantages and learns representations with both strong instance discriminability and local perceptibility. Specifically, CMAE consists of two branches where the online branch is an asymmetric encoder-decoder and the momentum branch is a momentum updated encoder. During training, the online encoder reconstructs original images from latent representations of masked images to learn holistic features. The momentum encoder, fed with the full images, enhances the feature discriminability via contrastive learning with its online counterpart. To make CL compatible with MIM, CMAE introduces two new components, i.e., pixel shifting for generating plausible positive views and feature decoder for complementing features of contrastive pairs. Thanks to these novel designs, CMAE effectively improves the representation quality and transfer performance over its MIM counterpart. CMAE achieves the state-of-the-art performance on highly competitive benchmarks of image classification, semantic segmentation and object detection. Notably, CMAE-Base achieves 85.3% top-1 accuracy on ImageNet and 52.5% mIoU on ADE20k, surpassing previous best results by 0.7% and 1.8% respectively.

Physiological, Photosynthetic, and Transcriptomics Insights into the Influence of Shading on Leafy Sweet Potato.

Leafy sweet potato is a new type of sweet potato, whose leaves and stems are used as green vegetables. However, sweet potato tips can be affected by pre-harvest factors, especially the intensity of light. At present, intercropping, greenhouse planting, and photovoltaic agriculture have become common planting modes for sweet potato. Likewise, they can also cause insufficient light conditions or even low light stress. This research aimed to evaluate the influence of four different shading levels (no shading, 30%, 50%, and 70% shading degree) on the growth profile of sweet potato leaves. The net photosynthetic rate, chlorophyll pigments, carbohydrates, and polyphenol components were determined. Our findings displayed that shading reduced the content of the soluble sugar, starch, and sucrose of leaves, as well as the yield and Pn. The concentrations of Chl a, Chl b, and total Chl were increased and the Chl a/b ratio was decreased for the more efficient interception and absorption of light under shading conditions. In addition, 30% and 50% shading increased the total phenolic, total flavonoids, and chlorogenic acid. Transcriptome analysis indicated that genes related to the antioxidant, secondary metabolism of phenols and flavonoids, photosynthesis, and MAPK signaling pathway were altered in response to shading stresses. We concluded that 30% shading induced a high expression of antioxidant genes, while genes related to the secondary metabolism of phenols and flavonoids were upregulated by 50% shading. And the MAPK signaling pathway was modulated under 70% shading, and most stress-related genes were downregulated. Moreover, the genes involved in photosynthesis, such as chloroplast development, introns splicing, and Chlorophyll synthesis, were upregulated as shading levels increased. This research provides a new theoretical basis for understanding the tolerance and adaptation mechanism of leafy sweet potato in low light environments.

Microcolin H, a novel autophagy inducer, exerts potent antitumour activity by targeting PITPα/ß.

The identification of effective drug targets and the development of bioactive molecules are areas of high need in cancer therapy. The phosphatidylinositol transfer protein alpha/beta isoform (PITPα/ß) has been reported to play an essential role in integrating phosphoinositide trafficking and lipid metabolism in diverse cellular processes but remains unexplored as a potential target for cancer treatment. Herein, data analysis of clinical cancer samples revealed that PITPα/ß expression is closely correlated with the poor prognosis. Target identification by chemical proteomic methods revealed that microcolin H, a naturally occurring marine lipopeptide, directly binds PITPα/ß and displays antiproliferative activity on different types of tumour cell lines. Furthermore, we identified that microcolin H treatment increased the conversion of LC3I to LC3II, accompanied by a reduction of the level of p62 in cancer cells, leading to autophagic cell death. Moreover, microcolin H showed preeminent antitumour efficacy in nude mouse subcutaneous tumour models with low toxicity. Our discoveries revealed that by targeting PITPα/ß, microcolin H induced autophagic cell death in tumours with efficient anti-proliferating activity, which sheds light on PITPα/ß as a promising therapeutic target for cancer treatment.

Development and application of diffusive gradients in thin films for in situ sampling of the organic UV filter 4-methylbenzylidene camphor (4-MBC) in waters.

4-Methylbenzylidene camphor (4-MBC), a typical organic UV filter (OUVF) in personal care products, is considered to be a potential endocrine disruptor due to its estrogenic activity and bioaccumulation. Although 4-MBC residues have been extensively identified in aquatic waters, little is known about their occurrence, levels, and potential risk in coastal waters. This study developed a reliable sampling approach, based on diffusive gradients in thin films (DGT) with XAD-2 as the binding agent, for monitoring 4-MBC in coastal waters. The diffusion coefficients of 4-MBC in freshwater and artificial seawater were 3.65 × 10-6 cm2/s and 3.83 × 10-6 cm2/s, respectively. XAD-2 binding gel showed rapid adsorption to 4-MBC. The accumulated masses of 4-MBC in XAD-2 DGT increased linearly with deployed time for 7 days in freshwater and seawater, which agreed well with theoretical predictions. The sampling performance was independent of ionic strength (0.0001-0.5 M), pH (4.0-8.5), and dissolved organic matter (0-20 mg/L). Field deployment in the river estuary and bathing beach showed that DGT-measured 4-MBC concentrations were consistent in comparison with grab sampling. Environmental risk assessment showed that 4-MBC may pose a medium risk to aquatic organisms based on computed risk quotient (RQ) values. Sewage discharge is the main source of 4-MBC risk, while the residue in recreation beaches contributes more significantly in summer. The established DGT sampling is suitable for seasonal monitoring, source identification, and risk assessment of 4-MBC in coastal waters.

Synthesis of Se polysaccharide catalyzed by sulfonic acid functionalized ionic liquids: Synergism effect of anion/cation.

The rational design and construction of controllable selenylation strategy are important for the study on the structure-activity relationship of Se polysaccharides. Herein, selenized Artemisia sphaerocephala polysaccharides (SePASs) were synthesized by using sulfonic acid functionalized ionic liquids (SFILs) as catalysts in order to study the regulation of the cation/anion constitute on the selenylation efficiency and Se polysaccharide structure. Impressively, SFILs could promote the efficient substitution of seleno-group on the polysaccharide backbone through the synergistic catalysis by cation/anions (Se content up to 5582.7 µg/g). Further, reaction mechanism and potential dissolution effect was supported by DFT calculation and polarized light microscopy. 13C NMR and FT-IR spectra analysis of SePASs exhibited that selenite existed in polysaccharides and the substitution position occured at C-6. SEC-MALLS, monosaccharide composition results revealed that strong acidity of SFILs lead to the driving forces toward low molecular mass polysaccharide fragments and synergistic effect of anion/cations in SFILs (-SO3H group of cations as proton donor, anions as nucleophile) showed regulation on average molecular mass. In addition, the strong attractions between the seleno-groups generated agglomeration of polysaccharide chain, which was proved by applying AFM analysis. Therefore, this work provided a new insight for manipulate Se content and MW of Se polysaccharides.

Guiqi Baizhu prescription ameliorates cytarabine-induced intestinal mucositis by targeting JAK2 to inhibit M1 macrophage polarization.

BACKGROUND: Intestinal mucositis (IM) is characterized by damage to the intestinal mucosa resulting from inhibition of epithelial cell division and loss of renewal capacity following anticancer chemotherapy and radiotherapy. Cytarabine (Ara-C), the main chemotherapy drug for the treatment of leukemia and lymphoma, is a frequent cause of IM. Guiqi Baizhu prescription (GQBZP) is a traditional Chinese medicine with anti-cancer and anti-inflammatory effects. PURPOSE: To determine if GQBZP can ameliorate Ara-C induced IM and identify and characterize the pharmacologic and pharmacodynamic mechanisms. STUDY DESIGN AND METHODS: IM was induced in mice with Ara-C and concurrently treated with orally administered GQBZP. Body weight and food intake was monitored, with HE staining to calculate ileal histomorphometric scoring and villus length/crypt depth. Immunoblotting was used to detect intestinal tissue inflammatory factors. M1 macrophages (M1) were labeled with CD86 by flow cytometry and iNOS + F4/80 by immunofluorescence. Virtual screening was used to find potentially active compounds in GQBZP that targeted JAK2. In vitro, RAW264.7 cells were skewed to M1 macrophage polarization by lipopolysaccharide (LPS) and interferon-γ (INF-γ) and treated orally with GQBZP or potential active compounds. M1 was labeled with CD86 by flow cytometry and iNOS by immunofluorescence. ELISA was used to detect inflammatory factor expression. Active compounds against JAK2, p-JAK2, STAT1 and p-STAT1 were identified by western blotting and HCS fluorescence. Molecular dynamics simulations and pharmacokinetic predictions were carried out on representative active compounds. RESULTS: Experimental results with mice in vivo suggest that GQBZP significantly attenuated Ara-C-induced ileal damage and release of pro-inflammatory factors by inhibiting macrophage polarization to M1. Molecular docking was used to identify potentially active compounds in GQBZP that targeted JAK2, a key factor in macrophage polarization to M1. By examining the main components of each herb and applying Lipinski's rules, ten potentially active compounds were identified. In vitro experimental results suggested that all 10 compounds of GQBZP targeted JAK2 and could inhibit M1 polarization in RAW264.7 cells treated with LPS and INF-γ. Among them, acridine and senkyunolide A down-regulated the expression of JAK2 and STAT1. MD simulations revealed that acridine and senkyunolide A were stable in the active site of JAK2 and exhibited good interactions with the surrounding amino acids. CONCLUSIONS: GQBZP can ameliorate Ara-C-induced IM by reducing macrophage polarization to M1, and acridine and senkyunolide A are representative active compounds in GQBZP that target JAK2 to inhibit M1 polarization. Targeting JAK2 to regulate M1 polarization may be a valuable therapeutic strategy for IM.

Efficacy of bronchoscopic intratumoral injection of endostar and cisplatin in lung squamous cell carcinoma patients underwent conventional chemoradiotherapy.

Bronchoscopy has been widely used for the therapy of lung cancer. This study aimed to evaluate the therapeutic efficacy and adverse reactions of bronchoscopic intratumoral injection of endostar and cisplatin in patients with lung squamous cell carcinoma (LSCC). A total of 40 LSCC patients who underwent conventional chemoradiotherapy were included in this study, and 20 of them received a bronchoscopic injection of endostar and cisplatin as an additive therapeutic modality (treatment group). The clinical response rate, progression-free survival (PFS), and adverse reactions of the patients were compared and analyzed. The treatment group had better short- and long-term therapeutic efficacy compared to the control group, but no significant differences were observed between the two therapeutic regimens in adverse reactions. Elderly and advanced LSCC patients had worse therapeutic efficacy and a high probability of adverse reactions after the therapy. Collectively, our analysis data demonstrated that the bronchoscopic intratumoral injection of endostar and cisplatin had improved therapeutic efficacy, and the cardiovascular adverse reactions were within the controllable range in the treatment of LSCC in clinical practices.

Synthesis and Biological Evaluation of Gentiopicroside Derivatives as Novel Cyclooxygenase-2 Inhibitors with Anti-Inflammatory Activity.

Purpose: Nonsteroidal anti-inflammatory drugs cause a series of adverse reactions. Thus, the search for new cyclooxygenase-2 selective inhibitors have become the main direction of research on anti-inflammatory drugs. Gentiopicroside is a novel selective inhibitor of cyclooxygenase-2 from Chinese herbal medicine. However, it is highly hydrophilic owing to the presence of the sugar fragment in its structure that reduces its oral bioavailability and limits efficacy. This study aimed to design and synthesize novel cyclooxygenase-2 inhibitors by modifying gentiopicroside structure and reducing its polarity. Materials and Methods: We introduced hydrophobic acyl chloride into the gentiopicroside structure to reduce its hydrophilicity and obtained some new derivatives. Their in vitro anti-inflammatory activities were evaluated against NO, TNF-α, PGE2, and IL-6 production in the mouse macrophage cell line RAW264.7 stimulated by lipopolysaccharide. The in vivo inhibitory activities were further tested against xylene-induced mouse ear swelling. Molecular docking predicted that whether new compounds could effectively bind to target protein cyclooxygenase-2. The inhibitory activity of new compounds to cyclooxygenase-2 enzyme were verified by the in vitro experiment. Results: A total of 21 novel derivatives were synthesized, and exhibit lower polarities than the gentiopicroside. Most compounds have good in vitro anti-inflammatory activity. The in vivo activity results demonstrated that 8 compounds were more active than gentiopicroside. The inhibition rate of some compounds was higher than celecoxib. Molecular docking predicted that 6 compounds could bind to cyclooxygenase-2 and had high docking scores in accordance with their potency of the anti-inflammatory activity. The confirmatory experiment proved that these 6 compounds had significant inhibitory effect against cyclooxygenase-2 enzyme. Structure-activity relationship analysis presumed that the para-substitution with the electron-withdrawing groups may benefit the anti-inflammatory activity. Conclusion: These gentiopicroside derivatives especially PL-2, PL-7 and PL-8 may represent a novel class of cyclooxygenase-2 inhibitors and could thus be developed as new anti-inflammatory agents.

Dual Proton/Silver-Catalyzed Serial (5 + 2)-Cycloaddition and Nazarov Cyclization of (E)-2-Arylidene-3-hydroxyindanones with Conjugated Eneynes: Synthesis of Indanone-Fused Benzo[cd]azulenes.

A one-pot step-economic tandem process involving (5 + 2)-cycloaddition and Nazarov cyclization reactions has been reported for the facile synthesis of indanone-fused benzo[cd]azulenes from (E)-2-arylidene-3-hydroxyindanones and conjugated eneynes. This highly regio- and stereoselective bisannulation reaction is enabled by dual silver and Brønsted acid catalysis and opens up a new avenue for the construction of important bicyclo[5.3.0]decane skeletons.

Empirical and Theoretical Bases of Good Steamed Bread Production.

Chinese steamed bread (CSB) is a main staple food in China, accounting for 40% of wheat flour usage in China. Due to its health benefits, CSB is gaining popularity across the world. In this review, the effects of gluten proteins (particularly glutenins and gliadins) on the quality of CSB are summarized from the literature. Requirements of appropriate rheological parameters in different studies are compared and discussed. Along with the increasing demand for frozen storage food, there are obvious increases in the research on the dynamics of gluten proteins in frozen dough. This review also summarizes the factors influencing the deterioration of CSB dough quality during frozen storage as well as effective measures to mitigate the negative effects.

Tumor killing by a dietary curcumin mono-carbonyl analog that works as a selective ROS generator via TrxR inhibition.

In comparison with normal cells, cancer cells feature intrinsic oxidative stress, thereby being more vulnerable to further production of reactive oxygen species (ROS) by pro-oxidative anticancer agents (PAAs). However, PAAs also inevitably generate ROS in normal cells, resulting in their narrow therapeutic window and toxic side effects that greatly limit their clinical application. To develop PAAs that generate ROS selectively in cancer cells over in normal cells, we rationally designed three series of 21 dietary curcumin 5-carbon mono-carbonyl analogs differentiated by either placement of the cyclohexanone, piperidone, and methylpiperidone linkers, or introduction of electron-withdrawing trifluoromethyl and electron-donating methoxyl groups on its two aromatic rings in the ortho, meta, or para position to the linkers. From the designed molecules, 2c, characterized of the presence of the meta-CF3-substituted mode and the piperidone linker, was identified as a potent selective ROS-generating agent, allowing its ability to kill selectively human non-small cell lung cancer NCI-H460 (IC50 = 0.44 µM) over human normal lung MRC-5 cells with a selectivity index of 32.0. Additionally, it was more potent and selective than the conventional chemotherapeutic agents (5-fluorouracil and camptothecin) did. Mechanistical investigation reveals that by means of its Michael acceptor unit and structure characteristics as described above, 2c could covalently modify the Sec-498 residue of intracellular thioredoxin reductase (TrxR) to generate ROS selectively, resulting in ROS-dependent apoptosis and ferroptosis of NCI-H460 cells. Noticeably, 2c inhibited significantly the growth of NCI-H460 cell xenograft tumor in nude mice without obvious toxicity to liver and kidney. Together, this work highlights a practical strategy of targeting TrxR overexpressed in cancer cells to develop PAAs capable of generating ROS selectively, as evidenced by the example of 2c.

Astragaloside IV alleviates cytarabine-induced intestinal mucositis by remodeling macrophage polarization through AKT signaling.

BACKGROUND: Intestinal mucositis (IM) is one of the common side effects of chemotherapy with Cytarabine (Ara-C) and contributes to the major dose-limiting factor of chemotherapy, while the effective drug for IM is little. Astragalus, one of the main active components extrated from the roots of Astragalus membranaceus (AS-IV), is a common Chinese herbal medicine used in gastrointestinal diseases. However, the effect and mechanism of AS-IV on IM is unclear. Accumulating evidence suggests that M1 macrophages play a pivotal role in IM progression. PURPOSE: The purpose of the study was to explore the protection of AS-IV and its potential molecular mechanism on intestinal mucositis injury induced by Ara-C. METHOD: The protective effect of AS-IV was investigated in LPS-induced macrophages and Ara-C-induced intestinal mucositis mouse model. H&E, immunofluorescence and western blotting were used to evaluate the damage in different doses of Ara-C. Silencing AKT targeted by siRNA was performed to explore the potential mechanisms regulating macrophage polarization effect of Ara-C, which was investigated by CCK-8, immunofluorescence and western blotting. Flow cytometry, immunofluorescence and Western blotting were used to detect macrophage surface marker proteins and inflammatory genes to explore the potential molecular mechanism of AS-IV regulating macrophage polarization. RESULTS: The Cytarabine intervention at dose of 100mg/kg significantly induced IM in mice, with the ileum the most obvious site of injury, accompanied by decreased intestinal barrier, intestinal macrophage polarization to M1 and inflammation response. The administration of AS-IV improved weight loss, food intake, ileal morphological damage, intestinal barrier destruction and inflammatory factor release in mice induced by Ara-c, and also suppressed macrophage polarization to M1, regulating in phenotypic changes in macrophages. In vitro, the expression of M1 macrophage surface marker protein was markedly decreased in LPS-induced macrophages after silencing AKT. Similarly, the western blotting of intestinal tissues and molecular docking indicated that the key mechanisms of AS-IV were remodel AKT signaling, and finally regulating M1 macrophages and decrease inflammation response. CONCLUSION: Our study highlights that AS-IV exerts protective effect in Ara-C-induced IM through inhibit polarization to M1 macrophages based on AKT, and AS-IV may serve as a novel AKT inhibitor to counteract the intestinal adverse effects of chemotherapeutic agents.