Unveiling the Mechanism of the ChaiShao Shugan Formula Against Triple-Negative Breast Cancer.

Background: The ChaiShao Shugan Formula (CSSGF) is a traditional Chinese medicine formula with recently identified therapeutic value in triple-negative breast cancer (TNBC). This study aimed to elucidate the underlying mechanism of CSSGF in TNBC treatment. Methods: TNBC targets were analyzed using R and data were from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The major ingredients and related protein targets of CSSGF were explored via the Traditional Chinese Medicine Systems Pharmacology database, and an ingredient-target network was constructed via Cytoscape to identify hub genes. The STRING database was used to construct the PPI network. GO and KEGG enrichment analyses were performed via R to obtain the main targets. The online tool Kaplan‒Meier plotter was used to identify the prognostic genes. Molecular docking was applied to the core target genes and active ingredients. MDA-MB-231 and MCF-7 cell lines were used to verify the efficacy of the various drugs. Results: A total of 4562 genes were screened as TNBC target genes. The PPI network consisted of 89 nodes and 845 edges. Our study indicated that quercetin, beta-sitosterol, luteolin and catechin might be the core ingredients of CSSGF, and EGFR and c-Myc might be the latent therapeutic targets of CSSGF in the treatment of TNBC. GO and KEGG analyses indicated that the anticancer effect of CSSGF on TNBC was mainly associated with DNA binding, transcription factor binding, and other biological processes. The related signaling pathways mainly involved the TNF-a, IL-17, and apoptosis pathways. The molecular docking data indicated that quercetin, beta-sitosterol, luteolin, and catechin had high affinity for EGFR, JUN, Caspase-3 and ESR1, respectively. In vitro, we found that CSSGF could suppress the expression of c-Myc or promote the expression of EGFR. In addition, we found that quercetin downregulates c-Myc expression in two BC cell lines. Conclusion: This study revealed the effective ingredients and latent molecular mechanism of action of CSSGF against TNBC and confirmed that quercetin could target c-Myc to induce anti-BC effects.

Soil differentiation and soil comprehensive evaluation of in wild and cultivated Fritillaria pallidiflora Schrenk.

Few studies have focused on the growth, soil quality and sustainability of medicinal plants under different soil conditions. In this study, the spatial heterogeneity of soil physical and chemical properties, the diversity of rhizosphere soil microbial community structure, and the characteristics of growth of the wild and cultivated medicinal plant, Siberian fritillary (Fritillaria pallidiflora Schrek) were analyzed, and the soil quality and ecosystem sustainability were comprehensively evaluated. The results showed that there was significant spatial variability of soil nutrients in the different habitats. Nitrate nitrogen (NO3-N) was strongly variable, while those of the soil organic carbon (SOC) and available phosphorus (AP) were moderately variable. There was little variability among the soil available potassium (AK), electrical conductivity (EC), pH and ammonium nitrogen (NH4-N). Inverse Distance Weighting spatial interpolation showed that SOC, NO3-N, NH4-H and EC were highly distributed in the southeastern part of the wild area, and the soil was more acidic in the original habitat than in the planting habitat. There was little AK and AP in the native habitat, and there was a high content in the planting habitat. Simultaneously, the soil microbial communities of the two soils also differed. The wild-type soil showed a "fungal" type, while the planted soil showed a "bacterial" type. Pathogenic bacteria were among the primary microflora in the planting area. In general, it is difficult to maintain the sustainable development and geo-herbalism of F. pallidiflora in today's cultivation mode because of the significant differences in soil nature, spatial heterogeneity and microbial community structure for the growth of F. pallidiflora. Therefore, future planting should focus on transforming it from intensive to mountain forest planting. This is highly significant for improving the planting efficiency of F. pallidiflora, protecting their geo-herbalism and germplasm resources, and maintaining the stability and sustainable development of the ecosystem.

Anthraquinones with potential antiproliferative activities from the fruits of Morinda citrifolia.

The phytochemical investigation on the fruits of Morinda citrifolia led to the isolation and characterization of a new anthraquinone, moricitrifone (1), along with seven known anthraquinones (2-8). The chemical structure of 1 was elucidated by extensive spectral analyses. The known compounds (2-8) were identified by comparing their spectral data with those reported in the literature. The antiproliferative activities of all isolated anthraquinones (1-8) against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 were evaluated in vitro. Compounds 1-8 exhibited remarkable antiproliferative activities with IC50 values ranging from 0.26 ± 0.05 to 16.58 ± 0.18 µM, which were comparable to those of doxorubicin.

Structure-guided preparation of fuctional oil rich in 1,3-diacylglycerols and linoleic acid from Camellia oil by combi-lipase.

BACKGROUND: Diacylglycerol (DAG)-enriched oil has been attracting attention because of its nutritional benefits and biological functions, although the composition of its various free fatty acids (FFAs) and an unclear relationship between substrate and yield make it difficult to be identified and qualified with respect to its production. In the present study, linoleic acid-enriched diacylglycerol (LA-DAG) was synthesized and enriched from Camellia oil by the esterification process using the combi-lipase Lipozyme TL IM/RM IM system. RESULTS: The relationship between FFA composition and DAG species productivity was revealed. The results showed that heterogeneous FFA with a major constituent (more than 50%) exhibited higher DAG productivity and inhibited triacylglycerol productivity compared to homogeneous constituents. Joint characterization by high-performance liquid chromatography-evaporative light scattering detection, gas chromatography-mass spectrometry and ultra-performance liquid chromatography-heated electrospray ionization-tandem mass spectrometry identified that DAG components contained dilinoleic acid acyl glyceride, linoleyl-oleyl glyceride and dioleic acid acyl glyceride in esterification products. Under the optimum conditions, 60.4% 1,3-DAG and 61.3% LA-DAG in the crude product at 1 h reaction were obtained, and further purified to 81.7% LA-DAG and 94.7% DAG via silica column chromatography. CONCLUSION: The present study provides a guideline for the identification of DAG species, as well as a structure-guided preparation method of DAG-enriched oils via the cost-effective combi-lipase. © 2022 Society of Chemical Industry.

Uranium extraction from seawater: material design, emerging technologies and marine engineering.

Uranium extraction from seawater (UES), a potential approach to securing the long-term uranium supply and sustainability of nuclear energy, has experienced significant progress in the past decade. Promising adsorbents with record-high capacities have been developed by diverse innovative synthetic strategies, and scale-up marine field tests have been put forward by several countries. However, significant challenges remain in terms of the adsorbents' properties in complex marine environments, deployment methods, and the economic viability of current UES systems. This review presents an up-to-date overview of the latest advancements in the UES field, highlighting new insights into the mechanistic basis of UES and the methodologies towards the function-oriented development of uranium adsorbents with high adsorption capacity, selectivity, biofouling resistance, and durability. A distinctive emphasis is placed on emerging electrochemical and photochemical strategies that have been employed to develop efficient UES systems. The most recent achievements in marine tests by the major countries are summarized. Challenges and perspectives related to the fundamental, technical, and engineering aspects of UES are discussed. This review is envisaged to inspire innovative ideas and bring technical solutions towards the development of technically and economically viable UES systems.

Photodynamic antitumor activity of Gallium(III) and Phosphorus(V) complexes of trimethoxyl A2B triaryl corrole.

Two new trimethoxyl A2B triaryl corroles 10-(2,4,6-trimethoxyphenyl)-5,15-bis(pentafluorophenyl)- corrole (1) and 10-(3,4,5-trimethoxyphenyl)-5,15-bis(pentafluorophenyl)-corrole (2) and their gallium(III) and phosphorus(V) (1-Ga, 1-P, 2-Ga and 2-P) complexes had been prepared and well characterized by UV-vis, NMR and HR-MS. Among all compounds, 2-Ga, 1-P and 2-P showed excellent in vivo photodynamic activity against the MDA-MB-231, A549, Hela and HepG2 cell lines upon light irradiation at 625 nm. And 2-P even exhibited higher phototoxicity than the clinical photosensitizer temoporfin. Also, 2-P exhibited the highest singlet oxygen quantum yield and photostability. The preliminary investigation revealed that 2-P could be rapidly absorbed by tumor cells and mainly located in the cytoplasm. After photodynamic therapy (PDT) treatment with 2-P, mitochondrial membrane potential destruction, intracellular ROS level increasing and nuclear fragmentation of cancer cells could be observed. Cell cycle analysis demonstrated that the 2-P PDT may cause tumor cell arrest at sub-G1 stage and induce early and late apoptosis of cells. These results suggest that 2-P is a promising candidate as a photosensitizer for photodynamic therapy.

Fabrication, characterization, and purification of nutraceutical diacylglycerol components from Camellia oil.

Converting triacylgycerols (TAGs) from edible oils and fats into structured diacylglycerols (DAGs) is meaningful for reducing obesity. Camellia oil, rich in linoleic acid, has the potential to form structured linoleic acid-1,3-diacylglycerol (LA-1,3-DAG) nutrients in the industry. In this research, the physicochemical properties of modified Camellia oil (MCO) by enzymatic esterification were analyzed by Gas Chromatography-Mass Spectrometry (GC-MS), Differential Scanning Calorimetry (DSC), High Performance Liquid Chromatography-Evaporative Light Scattering Detection (HPLC-ELSD), and Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS). The relationship between reaction conditions and the DAG compositions is disclosed using multiple factors. It is found that high constituents of DAG increase the melting and crystallization temperature of MCO, lipase Novozym 435 gives the best yield of targeted nutrients (DAG, 1,3-DAG, LA-DAG), and the mixture of lipases, Lipozyme TL IM and Lipozyme RM IM, shows a synergistic effect in the synthetic process of DAG. Subsequently, MCO containing 65.4% DAG, 54.7% LA-DAG, and 47.6% 1,3-DAG content at optimal conditions (2% enzyme dosage, 4 h reaction time, 2.4:1 substrate molar ratio, 25.8% t-butanol as solvent, 60°C temperature) has been obtained and purified using silica column to obtain the final DAG oil containing 96.1% DAG, 64.7% 1,3-DAG, and 78.4% LA-DAG. High constituents of structured DAG oil rich in LA-1,3-DAG can be obtained by enzymatic esterification for industrial production.

Functional drug-target-disease network analysis of gene-phenotype connectivity for curcumin in hepatocellular carcinoma.

BACKGROUND: The anti-tumor properties of curcumin have been demonstrated for many types of cancer. However, a systematic functional and biological analysis of its target proteins has yet to be fully documented. The aim of this study was to explore the underlying mechanisms of curcumin and broaden the perspective of targeted therapies. METHODS: Direct protein targets (DPTs) of curcumin were searched in the DrugBank database. Using the STRING database, the interactions between curcumin and DPTs and indirect protein targets (IPTs) weres documented. The protein-protein interaction (PPI) network of curcumin-mediated proteins was visualized using Cytoscape. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed for all curcumin-mediated proteins. Furthermore, the cancer targets were searched in the Comparative Toxicogenomics Database (CTD). The overlapping targets were studied using Kaplan-Meier analysis to evaluate cancer survival. Further genomic analysis of overlapping genes was conducted using the cBioPortal database. Lastly, MTT, quantitative polymerase chain reaction (qPCR), and western blot (WB) analysis were used to validate the predicted results on hepatocellular carcinoma (HCC) cells. RESULTS: A total of five DPTs and 199 IPTs were found. These protein targets were found in 121 molecular pathways analyzed via KEGG enrichment. Based on the anti-tumor properties of curcumin, two pathways were selected, including pathways in cancer (36 genes) and HCC (22 genes). Overlapping with 505 HCC-related gene sets identified in CTD, five genes (TP53, RB1, TGFB1, GSTP1, and GSTM1) were finally identified. High mRNA levels of TP53, RB1, and GSTM1 indicated a prolonged overall survival (OS) in HCC, whereas elevated mRNA levels of TGFB1 were correlated with poor prognosis. The viability of both HepG2 cells and Hep3B cells was significantly reduced by curcumin at concentrations of 20 or 30 µM after 48 or 72 h of culture. At a concentration of 20 µM curcumin cultured for 48 h, the expression of TGFB1 and GSTP1 in Hep3B cells was reduced significantly in qPCR analysis, and reduced TGFB1 protein expression was also found in Hep3B cells.

Oleic Acid Copolymer as A Novel Upconversion Nanomaterial to Make Doxorubicin-Loaded Nanomicelles with Dual Responsiveness to pH and NIR.

Oleic acid (OA) as main component of plant oil is an important solvent but seldom used in the nanocarrier of anticancer drugs because of strong hydrophobicity and little drug release. In order to develop a new type of OA nanomaterial with dual responses to pH and near infrared light (NIR) to achieve the intelligent delivery of anticancer drugs. The novel OA copolymer (mPEG-PEI-(NBS, OA)) was synthesized by grafting OA and o-nitrobenzyl succinate (NBS) onto mPEGylated polyethyleneimine (mPEG-PEI) by amidation reaction. It was further conjugated with NaYF4:Yb3+/Er3+ nanoparticles, and encapsulated doxorubicin (DOX) through self-assembly to make upconversion nanomicelles with dual response to pH and NIR. Drug release behavior of DOX, physicochemical characteristics of the nanomicelles were evaluated, along with its cytotoxic profile, as well as the degree of cellular uptake in A549 cells. The encapsulation efficiency and drug loading capacity of DOX in the nanomicelles were 73.84% ± 0.58% and 4.62% ± 0.28%, respectively, and the encapsulated DOX was quickly released in an acidic environment exposed to irradiation at 980 nm. The blank nanomicelles exhibited low cytotoxicity and excellent biocompatibility by MTT assay against A549 cells. The DOX-loaded nanomicelles showed remarkable cytotoxicity to A549 cells under NIR, and promoted the cellular uptake of DOX into the cytoplasm and nucleus of cancer cells. OA copolymer can effectively deliver DOX to cancer cells and achieve tumor targeting through a dual response to pH and NIR.

Electro-Acupuncture Promotes Accumulation of Paclitaxel by Altering Tumor Microvasculature and Microenvironment in Breast Cancer of Mice.

Targeted drug delivery could increase the efficacy of chemotherapy, however, a plethora of obstacles exist in the current targeted delivery designs. In this study, we introduce a novel avenue of targeted drug delivery using electro-acupuncture and evaluate its effect on the distribution of paclitaxel in a breast cancer mouse model. Our results show that electro-acupuncture intervention significantly increased the intratumoral concentration of paclitaxel. The mice in acupuncture group showed shorter t max, longer t 1/2 and higher AUC of paclitaxel as compared with that in paclitaxel-only group. Moreover, we found that the acupuncture intervention significantly induced cell apoptosis in tumors. The levels of COL IV and α-SMA increased in tumors of acupuncture group. The negative tumor metastasis biomarker, NM23, was significantly upregulated in tumors of mice in acupuncture group. Our results suggest that acupuncture intervention around the tumor area increases the local concentration of chemotherapeutic agents. The targeted effect of acupuncture is achieved by altering tumor microvasculature and microenvironment. Therefore, combined therapy of acupuncture with chemotherapeutic agents is promising in improving cancer treatment efficacy.

Loading of water-insoluble celastrol into niosome hydrogels for improved topical permeation and anti-psoriasis activity.

Psoriasis is a severe disfiguring skin disease affecting approximately 3% of people worldwide and negatively affecting their daily lives. The pathogenesis of psoriasis is complicated, and typical therapeutic strategies for psoriasis mainly focus on anti-inflammation. Considering the side effects, withdrawal rebound, high cost, and many other disadvantages of existing treatments, we developed a new topical therapeutic formulation consisting of niosomes loaded with celastrol, a triterpenoid extracted from Tripterygium. Celastrol niosomes were prepared by the thin film hydration method and probe sonication. The niosomes were composed of Span 20, Span 60, and cholesterol at a weight ratio of 3:1:1. The particle size of the niosomes was approximately 147 nm, with yield of up to 90%. Celastrol niosomes showed improved in vitro permeation ability compared to the raw drug. In our in vivo study, celastrol niosomes effectively alleviated erythema and scaling on the dorsal skin of psoriasis mouse models. Spleen weight and the levels of cytokines, including IL-22, IL-23, and IL-17, decreased after the treatment, indicating the high therapeutic potential of this formulation for psoriasis. In conclusion, encapsulation of celastrol by niosomes increased the water-solubility and permeation of celastrol into the skin, significantly improving its anti-psoriasis activity in mice.

Utilising network pharmacology to explore the underlying mechanism of Wumei Pill in treating pancreatic neoplasms.

BACKGROUND: Wumei Pill (WMP), a famous herbal formula, has been widely used to treat digestive system diseases in clinical practice in China for centuries. We have found a correlation between the indications of WMP and the typical symptoms of pancreatic neoplasms. However, the pharmacological mechanisms of WMP still remain unknown. METHODS: In the present work, we used a network pharmacological method to predict its underlying complex mechanism of treating pancreatic neoplasms. Firstly, we obtained relative compounds of WMP based on TCMSP database, TCM database@Taiwan and TCMID database and collected potential targets of these compounds by target fishing. Then we built the pancreatic neoplasms target database by CTD, TTD, PharmGKB. Based on the matching results between WMP potential targets and pancreatic neoplasms targets, we built a PPI network to analyze the interactions among these targets and screen the hub targets by topology. Furthermore, DAVID bioinformatics resources were utilized for the enrichment analysis on GO_BP and KEGG. RESULTS: A total of 80 active ingredients and 77 targets of WMP were picked out. The results of DAVID enrichment analysis indicated that 58 cellular biological processes (FDR < 0.01) and 17 pathways (FDR < 0.01) of WMP mostly participated in the complex treating effects associated with proliferation, apoptosis, inflammatory response and angiogenesis. Moreover, 17 hub nodes of WMP (PTGS2, BCL2, TP53, IL6, MAPK1, EGFR, EGF, CASP3, JUN, MAPK8, MMP9, VEGFA, TNF, MYC, AKT1, FOS and TGFB1) were recognized as potential targets of treatments, implying the underlying mechanisms of WMP acting on pancreatic neoplasms. CONCLUSION: WMP could alleviate the symptoms of pancreatic neoplasms through the molecular mechanisms predicted by network pharmacology. This study proposes a strategy to elucidate the mechanisms of Traditional Chinese Medicine (TCM) at the level of network pharmacology.

The plant triterpenoid celastrol blocks PINK1-dependent mitophagy by disrupting PINK1's association with the mitochondrial protein TOM20.

A critical function of the PTEN-induced kinase 1 (PINK1)-Parkin pathway is to mediate the clearing of unhealthy or damaged mitochondria via mitophagy. Loss of either PINK1 or Parkin protein expression is associated with Parkinson's disease. Here, using a high-throughput screening approach along with recombinant protein expression and kinase, immunoblotting, and immunofluorescence live-cell imaging assays, we report that celastrol, a pentacyclic triterpenoid isolated from extracts of the medicinal plant Tripterygium wilfordii, blocks recruitment pof Parkin to mitochondria, preventing mitophagy in response to mitochondrial depolarization induced by carbonyl cyanide m-chlorophenylhydrazone or to gamitrinib-induced inhibition of mitochondrial heat shock protein 90 (HSP90). Celastrol's effect on mitophagy was independent of its known role in microtubule disruption. Instead, we show that celastrol suppresses Parkin recruitment by inactivating PINK1 and preventing it from phosphorylating Parkin and also ubiquitin. We also observed that PINK1 directly and strongly associates with TOM20, a component of the translocase of outer mitochondrial membrane (TOM) machinery and relatively weak binding to another TOM subunit, TOM70. Moreover, celastrol disrupted binding between PINK1 and TOM20 both in vitro and in vivo but did not affect binding between TOM20 and TOM70. Using native gel analysis, we also show that celastrol disrupts PINK1 complex formation upon mitochondrial depolarization and sequesters PINK1 to high-molecular-weight protein aggregates. These results reveal that celastrol regulates the mitochondrial quality control pathway by interfering with PINK1-TOM20 binding.

Synthesis and study of three novel macrocyclic selena[n]ferrocenophanes containing a naphthalene unit.

Three novel macrocyclic ligands, L1-L3, in which a ferrocene unit and a fluorescent moiety are linked to polyselena rings have been designed and prepared from 1,1'-bis(3-bromopropylseleno)ferrocene. Reaction of L with [M(NCMe)4](PF6)2 (M = Pd and Pt) led to complexes [ML](PF6)2 (M = Pd and Pt). Crystal structure analysis revealed that after complexation, the macrocyclic ligand adopts the unusual c,c,c conformation due to intramolecular C-H···π interactions from the hydrogen atoms of ferrocene moieties to the naphthalene ring. Electrochemical studies showed that in [ML](PF6)2 (M = Pd and Pt) the half-wave potential of the 1,1'-ferrocenediyl group shifts to much more positive potentials due to electron density withdrawn from Se donor atoms. Electrochemical and optical measurements were used to calculate HOMO and LUMO levels as well as HOMO-LUMO band gaps. Results were compared and correlated with the differences in molecular structures.

[United Plackett-Burman and Box-Behnken design to control formation of indirubin in process of preparing indigo naturalis].

OBJECTIVE: To screen the factors that affect indirubin-generated significantly in the process of preparing indigo naturalis, optimize level combination and determine the optimum technology for indirubin-generated. METHOD: Using concentration of indirubin (mg x g(-1)) that generated by fresh leaf as an index, Plackett-Burman design, Box-Behnken design response surface analysis as the statistical method, we screened the significantly influencing factors and the optimal level combination. RESULT: The soaking and making indirubin process in preparing indigo naturalis was identified as the wax is not removed before immersion with immersion pH 7, solvent volume-leaf weight (mL: g)15, soaked not avoided light, soaking 48 h, temperature 60 degrees C, ventilation time of 180 min, and added ammonia water to adjust pH to 10.5. CONCLUSION: The soaking and making indirubin process in preparing indigo naturalis is optimized systematically. It clarify the various factors on the impact of the active ingredient indirubin which controlled by industrialized production become reality in the process of preparing indigo naturalis, at the same time, it lay the foundation for processing principle of indigo naturalis.

[Study on mechanism of precursors transforming into indigo and indirubin in blue-genera plants].

Accessed to literatures at home and abroad, we introduced the process of indigo naturalis transforming from dyestuff industry into pharmaceutical industry. It is affirmed that the precursors of indigo and indirubin are isatan A, isatan B, isatan C and indicant. Meanwhile, author clarified the mechanism of transformation for these precursors transforming into indigo and indirubin. And we summarized methods of determination for these precursors. In summary, these references provide us accordance of study on processing principle of Indigo naturalis, and lay the foundation for technics of making indigo and indirubin entering into modern industry.

Evaluation of the efficacy and safety of a statin/caffeine combination against H5N1, H3N2 and H1N1 virus infection in BALB/c mice.

The development of novel antiviral drugs is necessary for the prevention and treatment of a potential avian influenza pandemic. The aim of this study was to evaluate the efficacy and safety of a novel statin/caffeine combination against H5N1, H3N2 and H1N1 virus infection in a murine model. In H5N1-, H3N2- and H1N1-infected BALB/c mice, 50mug statin/200mug caffeine effectively ameliorated lung damage and inhibited viral replication and was at least as effective as oseltamivir and ribavirin. The statin/caffeine combination also appeared to be more effective when administered preventatively rather than as treatment. These findings provide justification for further research into this novel antiviral formulation.