Background
Glycyrrhetinic acid (GA) derivatives had shown not only cytotoxicity but also could trigger apoptosis in various human cancer cell lines. Moreover, cinnamic acid (CA) and its phenolic ...analogues as potent antitumor agents were employed in the design of anti-tumor drugs. To further improve the anti-tumor activity of GA and CA derivatives, a series of novel compounds were designed and synthesized using GA and CA derivatives fragments.
Results
The result showed that all the novel glycyrrhetinic acid-cinnamoyl (GA–CA) hybrids presented higher antitumor activity on the tumor cell lines of HepG2, HT-29, Hela and lower cytotoxicity on three non-tumor cells lines MDCK, HY926, H9C2 than the parent compounds (IC
50
> 50 μM). It was worth noting that
8a
had a superior cytotoxicity effect on Hela cells (IC
50
= 8.54 μM) than on other cancer cell lines (IC
50
> 15 μM). And it also indicated that
8a
showed lower cytotoxicity (IC
50
> 27 μM) towards MDCK, HY926 and H9C2 cells than cisplatin (DDP, IC
50
< 10 μM). Moreover, according to the acute toxicity, it could be indicated that the LD
50
of
8a
exceeded 3.0 g/kg by oral administration in mice. The further research using Giemsa, H33342 staining, flow cytometric analysis and caspase-3 assay showed that
8a
could cause Hela cell damage, nuclei lysis and apoptosis. In addition, the structure–activity relationships of these hybrids were briefly discussed.
Conclusions
Compared with GA, target compounds demonstrated better anti-tumor activity, among which
8a
was the most active one. What’s more, structure–activity relationship analysis also revealed that hybrids with
trans
olefinic bond group show higher antitumor activity than those without olefinic bond, such as
1a
>
1b
,
6a
>
2b
,
8a
>
3b
,
9a
>
4b
. In addition, it was found that the methoxy substituent might enhance selectivity of GA–CA hybrids towards regular non-cancerous cells MDCK, HY926 and H9C2, such as
4a
,
6a
,
7a
,
8a
. However, there might be less relationship between the cytotoxicity and the quantity, position of methoxy moiety. Hence, it is urgent need to synthesize efficient, low toxicity and multi-target anti-tumor compounds based on the structure combination principle.
Dendrobium chrysotoxum Lindl, a well-known traditional Chinese medicinal herb used in the treatment of gastric disease, is distinguished as the first of the “nine immortal grasses”. Dendrobium ...chrysotoxum Lindl and the traditional Chinese medicine prescriptions containing Dendrobium chrysotoxum Lindl are often prescribed clinically to treat chronic gastritis and precancerous lesions of gastric cancer (PLGC), showing favorable clinical effects and medicinal value in the prevention of gastric cancer. However, the effective ingredients and pharmacological mechanisms through which Dendrobium chrysotoxum Lindl prevents and treats PLGC have not been adequately identified or interpreted.
The present study aimed to evaluate the effective ingredients and pharmacological mechanisms of Dendrobium chrysotoxum Lindl in the prevention and treatment of PLGC using network pharmacology. In addition, in vitro verification was performed to evaluate the mechanism of action of Erianin, the main active ingredient in Dendrobium chrysotoxum Lindl, providing experimental evidence for the clinical use of Dendrobium chrysotoxum Lindl in the treatment of PLGC.
Using network pharmacology methods, the main ingredients in Dendrobium chrysotoxum Lindl were screened from the ETCM, BATMAN-TCM, and TCMID databases, and their potential targets were predicted using the Swiss Target Prediction platform. The targets related to PLGC were retrieved through the GeneCard database, and the targets common to the main ingredients of Dendrobium chrysotoxum Lindl and PLGC were analyzed. The protein-protein interaction (PPI) network was obtained via the STRING database and analyzed visually using Cytoscape 3.7.2. The underlying mechanisms of the common targets identified through gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were analyzed using DAVID online. The “component-target-pathway” networks of Dendrobium chrysotoxum Lindl and Erianin were visually constructed by Cytoscape 3.7.2. The biological activity evaluation of Erianin's effect on PLGC was carried out using MC cell lines, the PLGC cell model established using MNNG to induce damage in normal gastric mucosal epithelial cell (GES-1). After the intervention of different concentrations of Erianin, MC cell viability was explored using the MTT assays, cell migration was determined by wound healing assays, the cell cycle and apoptosis were analyzed using flow cytometry, and the expression levels of related proteins and their phosphorylation in the HRAS-PI3K-AKT signaling pathway were detected by Western blot.
The “component-target-pathway” network constructed in this study showed 37 active ingredients from Dendrobium chrysotoxum Lindl and 142 overlapping targets related to both Dendrobium chrysotoxum Lindl and PLGC. The targets were associated with a variety of cancer-related signaling pathways, including Pathways in cancer, PI3K-Akt signaling pathway, Rap1 signaling pathway, Focal adhesion, Ras signaling pathway, and MAPK signaling pathway. Notably, the network showed that Erianin, the primary active ingredient from Dendrobium chrysotoxum Lindl and the component associated with the most targets, could regulate Pathways in cancer, PI3K-AKT signaling pathway, Focal adhesion, Rap1 signaling pathway, cell cycle, and RAS signaling pathway in the treatment of PLGC. Verification through in vitro experiments found that Erianin can significantly inhibit MC cell viability, inhibit cell migration, block the cell cycle in the G2/M phase, and induce cell apoptosis in a dose-dependent manner. The results of the Western blot experiment further showed that Erianin can significantly decrease the protein expression levels of HRAS, AKT, p-AKT, MDM2, Cyclin D1, and p-Gsk3β, and increase the protein expression level of p21, which suggests that Erianin can treat PLGC by regulating the HRAS-PI3K-AKT signaling pathway.
This study explained the positive characteristics of multi-component, multi-target, and multi-approach intervention with Dendrobium chrysotoxum Lindl in the treatment of PLGC. Our results suggest that Erianin may be a promising candidate in the development of prevention and treatment methods for PLGC. This study provided experimental evidence for the clinical use of Dendrobium chrysotoxum Lindl to treat PLGC and prevent gastric cancer.
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The ubiquity of amino antioxidants (AAOs) in the environment has attracted increasing attention, given their potential toxicity. This investigation represents a pioneering effort, systematically ...scrutinizing the toxicological effects of four distinct AAOs across the developmental spectrum of zebrafish, encompassing embryonic, larvae, and adult stages. The results indicate that four types of AAO exhibit varying degrees of cell proliferation toxicity. Although environmentally relevant concentrations of AAOs exhibit a comparatively circumscribed impact on zebrafish embryo development, heightened concentrations (300 μg/L) of N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) and N-isopropyl-N′-phenyl-p-phenylenediamine (IPPD) distinctly evoke developmental toxicity. Behavioral analysis results indicate that at concentrations of 20 and 300 μg/L, the majority of AAOs significantly reduced the swimming speed and activity of larvae. Moreover, each AAO triggers the generation of reactive oxygen species (ROS) in larvae, instigating diverse levels of oxidative stress. The study delineates parallel toxicological patterns in zebrafish exposed to 300 μg/L of 6PPD and IPPD, thereby establishing a comparable toxicity profile. The comprehensive toxicity effects among the four AAOs is as follows: IPPD >6PPD > N-Phenyl-1-naphthylamine (PANA) > diphenylamine (DPA). These findings not only enrich our comprehension of the potential hazards associated with AAOs but also provide data support for structure-based toxicity prediction models.
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•The 96 h LC50 of AAOs for zebrafish embryos is higher than that for adults.•AAOs can induce varying degrees of developmental toxicity in zebrafish embryos.•The most pronounced behavioral impact on larvae is observed with 6PPD and IPPD.•The overall toxicity of AAOs is in the following order: IPPD >6PPD > PANA > DPA.
Nitrogen oxide (NOx) emission from cement industry has caused severe atmospheric pollution for low denitration efficiency of existing denitration technologies. To tackle down this problem, an ...innovative NOx reduction method exhibiting a higher denitration efficiency was developed in this study to satisfy the requirement of cleaner production. Besides, its specific mechanism was clarified in a bench scale experimental setup while its commercial viability was verified in a demonstration project. In accordance with the method, the pulverized coal was first pretreated in a specially designed pretreater where partial fuel nitrogen was in-situ reduced to N2. Subsequently, products of pretreatment that exhibited higher chemical activity were injected to the precalciner to further reduce formed NOx in the kiln gas. As revealed from the results, the denitration efficiency of the novel method can reach to 60%∼80%. Besides, it is promising in industrial application for the easy on-site implementation, high denitration efficiency and incomparable cost advantage. Under the premise of NOx that dropped largely, the costs of initial investment and operation were overly small. It is therefore revealed that the proposed approach outperforms many of the existing denitration technologies in technological and environmental indicators, as well as from the economical perspective.
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•An innovative NOx reduction method is proposed and its mechanism is clarified.•Fuel nitrogen is pre-removed while reducing property of coal is enhanced.•Selecting correct air coefficient is a key factor for NOx reduction in the method.•The method has application prospect for price competitive and high efficiency.
•A two-process clinker manufacturing method using fluidized bed reactor is raised.•High heating rate and fluidization contribute to the formation of C2S.•Optimal operation conditions are summarized ...for the pretreatment process.
The cement industry is now confronted with the pressure of strict requirements of energy consumption and pollution emission. To solve the problem, a two-process clinker manufacturing method consisting of a pretreatment process and a final calcination process is raised. The new method uses fluidized bed reactors to substitute the rotary kiln and cyclone preheater. Applicable operation conditions of the brand-new pretreatment process are firstly investigated to make sure the method will succeed. The intermediate product is used to describe the material obtained from the pretreatment process. Influences of the variants including calcination temperature, calcination time, and calcination atmosphere on the formation of intermediate products were discussed in the study. Results showed that the amount of C2S (dicalcium silicate) and strength of the intermediate product particles increased with the rising temperature. The superiority of rapid heating and fluidization in the pretreatment process was illustrated by comparing three heating styles. The recommended sequence of calcination was fluidized bed calcination > rapid calcination > slow calcination. Calcined for 10 min at 1200 °C is the optimal condition for the pretreatment process. The influence of atmospheres on C2S formation was not obvious. Operation conditions of the pretreatment process were determined for further study.
Antibiotic resistance genes (ARGs) are emerging environmental pollutants, influenced by complex regulatory factors. River-lake systems act as natural reservoirs for ARGs and provide an ideal model ...for studying their regulatory mechanisms. This study employed high-throughput quantitative PCR, high-throughput sequencing, correlation analyses, and model predictions to investigate the dynamics of ARGs and their influencing factors in Liangzi Lake, located in the mid-reaches of the Yangtze River. The research specifically centered on three environmental components: lake water, sediment, and river water. Results indicated that the ARGs from eight major antibiotic classes, displaying distinct seasonal distribution patterns. In comparison to the sediment, the water phase demonstrated a higher diversity of ARGs, with the highest level of ARGs sharing observed between lake and river waters (approximately 83.7 %). Furthermore, seasonal variations significantly influenced the distributions of both ARGs and bacterial communities. The diversity of ARGs was highest during the summer and autumn, and specific bacterial species exhibited robust correlations with ARGs (including matA/mel, aac (6')-Ib-03, and blaROB). It is worth noting that environmental attributes and bacterial diversity had the most substantial impact on the dynamic changes in ARGs. Lastly, source tracking analysis pinpointed that sediment as the primary source of ARGs in lake water, constituting 45 % to 48 % of the total ARGs. Our study provides a comprehensive analysis of ARGs and their influencing factors in the river-lake system of the middle reaches of the Yangtze River, with Liangzi Lake as a representative case.
•Encapsulation of CoMo6 POM within a modified MIL-101-NH2 MOF.•Remarkable desulfurization performance achieved for diesel fuels.•Maintained POM activity and improved stability in heterogeneous ...catalyst design.•A detailed mechanism was proposed for the biomimetic AODS process.
Flexible encapsulation of polyoxometalates (POMs) into metal–organic frameworks (MOFs) is a promising and emerging research area. Herein, a novel non-homogeneous IL(CoMo6)-MIL-101-NH2 catalyst was prepared by a stepwise modification method, in which the unprecedentedly flexible encapsulation of POM-MOF catalyst was achieved through ion exchange of introducing (NH4)3H6CoMo6O24 into IL(Br)-MIL-101-NH2. This approach firmly encases the POM within the pores of MIL-101 through electrostatic interactions. It not only preserved the catalytic activity of POM, but also provided sufficient space for the reaction to occur. The IL(CoMo6)-MIL-101-NH2 catalyst retained a high similar activity to homogeneous catalyst, while possessing characteristics of a multiphase catalyst for easy separation and recovery. It tackles POM's solubility issue and enables its encapsulation in MOFs for heterogeneous catalysis. Furthermore, the unparalleled catalyst was utilized in a biomimetic approach for coupling with deep eutectic solvents to achieve ultra-deep aerobic oxidative desulfurization of diesel.
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•A metal- and alkali-free system consisting of NHPI and DES was developed.•Multiple hydrogen bond interactions played a crucial role in catalytic process.•The excellent activity with ...100% HMF conversion and 96% FFCA yield achieved.•NHPI displays exceptional activity without any additional electronic promoter.
The oxidation of 5-hydroxymethylfurfural (HMF) to produce high value-added 5-formyl-2-furancarboxylic acid (FFCA) represents a promising biomass conversion reaction that holds potential for biomass-based material for the drug synthesis and polyester industry. The present study presents a metal-free and alkali-free catalytic system consisting of N-hydroxyphthalimide (NHPI) as an organic molecule and a deep eutectic solvent (DES). This system was successfully employed for the aerobic oxidation process of HMF to FFCA, demonstrating exceptional catalytic activity with 100% conversion and 96% FFCA yield in the absence of any alkali. Multiple hydrogen bond interactions were found to be indispensable and play a crucial role in promoting the catalytic process. These H-bond interactions serve three essential purposes: facilitating the formation of deep eutectic solvents (DESs) between polyethylene glycol and tetrabutylammonium chloride, accelerating the dissolution and activation of HMF, and aiding in the generation of active free radicals for NHPI. This work demonstrated the predominant oxidation ability of the NHPI-DESs system for the oxidation of HMF to FFCA through hydrogen bond interaction, thereby offering invaluable insights into the aerobic oxidation processes involving hydrocarbons or alcohols.
Moluodan concentrated pill (MLD) is a traditional herbal formula used in China for the treatment of chronic atrophic gastritis (CAG). However, its pharmacological mechanism of action remains unclear.
...The aim of this study was to investigate the therapeutic effect and mechanism of action of MLD in the treatment of CAG using network pharmacology and in vivo experiments.
The active compounds of MLD were determined using network pharmacology, utilizing various Chinese medicine databases such as the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, Traditional Chinese Medicine Integrated Database, Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine, and a comprehensive database of Traditional Chinese Medicine on Immuno-Oncology. The compounds found in the root of Anemone altaica Fisch. were extracted from the China National Knowledge Infrastructure literature database. Additionally, the Swiss Target Prediction database and Similarity Ensemble Approach were employed to identify the potential targets of these components. CAG-related targets were gathered from the GeneCards and DisGeNET databases. Protein-protein interactions (PPIs) of the genes associated with the drug-disease crossover were examined, and a core PPI network was constructed using the STRING database (version 11.5) and Cytoscape (version 3.7.2). A gene-pathway network was established to identify significant target genes and pathways through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Finally, based on these findings and existing data, the tumor necrosis factor (TNF) signaling pathway was selected for further validation through in vivo experiments.
A total of 724 active molecules in MLD yielded 961 identified target genes, of which 179 were found to be potentially associated with CAG. From the common targets, a PPI network revealed ten core targets. Enrichment analysis suggested that MLD may primarily target TNF and AKT in the treatment of CAG. Essential signaling pathways, such as the PI3K-AKT and TNF pathways, were found to be crucial for the therapeutic effects of MLD on CAG. Furthermore, potential interactions and crosstalk between these pathways were identified. Moreover, we confirmed that MLD effectively improved gastric mucosa atrophy and cellular ultrastructural damage, while increasing pepsinogen secretion and decreasing gastrin, somatostatin, and motilin levels. Subsequent molecular biology studies in rat models of CAG demonstrated that MLD treatment significantly reduced the expression levels of TNF-α, phosphatidylinositol 3′-kinase (PI3K), and phosphorylated Akt (P < 0.05). Notably, the expression of nuclear factor kappa-B (NF-κB) exhibited a contrasting trend (P < 0.05), potentially associated with the crucial tumor suppressor role of NF-κB p105.
This study provides evidence that MLD effectively alleviates stomach mucosal atrophy through modulation of the TNF/PI3K/AKT signaling pathway. These findings establish a solid theoretical foundation for the practical management of CAG.
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•A rat model of chronic atrophic gastritis was established by the MNNG multifactorial modeling method.•The efficacy and mechanism of Moluodan for chronic atrophic gastritis were revealed in vivo experiments for the first time.•Moluodan exerts gastric mucosal protective effects via the TNF/PI3K/AKT signaling pathway.
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