Gut microbiota mediated the individualized efficacy of Temozolomide via immunomodulation in glioma.

BACKGROUND: Temozolomide (TMZ) is the preferred chemotherapy strategy for glioma therapy. As a second-generation alkylating agent, TMZ provides superior oral bio-availability. However, limited response rate (less than 50%) and high incidence of drug resistance seriously restricts TMZ's application, there still lack of strategies to increase the chemotherapy sensitivity. METHODS: Luci-GL261 glioma orthotopic xenograft model combined bioluminescence imaging was utilized to evaluate the anti-tumor effect of TMZ and differentiate TMZ sensitive (S)/non-sensitive (NS) individuals. Integrated microbiomics and metabolomics analysis was applied to disentangle the involvement of gut bacteria in TMZ sensitivity. Spearman's correlation analysis was applied to test the association between fecal bacteria levels and pharmacodynamics indices. Antibiotics treatment combined TMZ treatment was used to confirm the involvement of gut microbiota in TMZ response. Flow cytometry analysis, ELISA and histopathology were used to explore the potential role of immunoregulation in gut microbiota mediated TMZ response. RESULTS: Firstly, gut bacteria composition was significantly altered during glioma development and TMZ treatment. Meanwhile, in vivo anti-cancer evaluation suggested a remarkable difference in chemotherapy efficacy after TMZ administration. Moreover, 16s rRNA gene sequencing and non-targeted metabolomics analysis revealed distinct different gut microbiota and immune infiltrating state between TMZ sensitive and non-sensitive mice, while abundance of differential gut bacteria and related metabolites was significantly correlated with TMZ pharmacodynamics indices. Further verification suggested that gut microbiota deletion by antibiotics treatment could accelerate glioma development, attenuate TMZ efficacy and inhibit immune cells (macrophage and CD8α+ T cell) recruitment. CONCLUSIONS: The current study confirmed the involvement of gut microbiota in glioma development and individualized TMZ efficacy via immunomodulation, hence gut bacteria may serve as a predictive biomarker as well as a therapeutic target for clinical TMZ application.

Complexation of Apigenin and Oxymatrine Leading to Enhanced Anti-inflammatory Activity.

Apigenin (APG) is a well-known dietary flavonoid with multiple bioactivities, but its poor aqueous solubility may result in low oral bioavailability and thus compromised therapeutic effects. In the present study, APG was complexed with oxymatrine (OMT), a natural quinolizidine alkaloid, for enhanced anti-inflammatory activity, and the related mechanisms in the interaction of APG with OMT were investigated. Fourier transform-infrared spectroscopy, fluorescence spectroscopy, Raman spectroscopy, and proton nuclear magnetic resonance spectroscopy characterizations demonstrated the occurrence of an APG-OMT complex formed at a molar ratio of 1:2. Then, molecular dynamics simulations and quantum chemical calculations were utilized to elucidate that hydrogen bonding, van der Waals forces, and hydrophobic effects were the main forces acting in the formation of the APG-OMT complex. Pharmacokinetic studies in rats demonstrated that the oral bioavailability of APG in the APG-OMT complex was significantly higher than that of APG alone. Finally, bioactivity evaluation in the lipopolysaccharide-induced acute inflammatory injury mouse models showed that the APG-OMT complex exhibited more potent anti-inflammatory effects than APG alone. This study confirmed that APG and OMT exerted enhanced anti-inflammatory effects through self-complexation, which may provide a novel strategy for improving the bioavailability and bioactivity of natural product mixtures.

[Prediction analysis of quality markers and resource evaluation of Artemisiae Argyi Folium based on chemical composition and network pharmacology].

This study is based on ultra-high-performance liquid chromatography(UPLC), gas chromatography-mass spectrometry(GC-MS), and network pharmacology methods to analyze and predict potential quality markers(Q-markers) of Artemisiae Argyi Folium. First, UPLC and GC-MS techniques were used to analyze the content of 12 non-volatile components and 8 volatile components in the leaves of 33 Artemisia argyi germplasm resources as candidate Q-markers. Subsequently, network pharmacology was employed to construct a "component-target-pathway-efficacy" network to screen out core Q-markers, and the biological activity of the markers was validated using molecular docking. Finally, cluster analysis and principal component analysis were performed on the content of Q-markers in the 33 A. argyi germplasm resources. The results showed that 18 candidate components, 60 targets, and 185 relationships were identified, which were associated with 72 pathways related to the treatment of 11 diseases and exhibited 5 other effects. Based on the combination of freedom and component specificity, six components, including eupatilin, cineole, ß-caryophyllene, dinatin, jaceosidin, and caryophyllene oxide were selected as potential Q-markers for Artemisiae Argyi Folium. According to the content of these six markers, cluster analysis divided the 33 A. argyi germplasm resources into three groups, and principal component analysis identified S14 as having the highest overall quality. This study provides a reference for exploring Q-markers of Artemisiae Argyi Folium, establishing a quality evaluation system, further studying its pharmacological mechanisms, and breeding new varieties.

[Effect of apigenin in combination with oxymatrine on non-small cell lung cancer and mechanism].

This study explores the effect of apigenin(APG), oxymatrine(OMT), and APG+OMT on the proliferation of non-small cell lung cancer cell lines and the underlying mechanisms. Cell counting kit-8(CCK-8) assay was used to detect the vitality of A549 and NCI-H1975 cells, and colony formation assay to evaluate the colony formation ability of the cells. EdU assay was employed to examine the proliferation of NCI-H1975 cells. RT-qPCR and Western blot were performed to detect the mRNA and protein expression of PLOD2. Molecular docking was carried out to explore the direct action ability and action sites between APG/OMT and PLOD2/EGFR. Western blot was used to study the expression of related proteins in EGFR pathway. The viability of A549 and NCI-H1975 cells was inhibited by APG and APG+OMT at 20, 40, and 80 µmol·L~(-1) in a dose-dependent manner. The colony formation ability of NCI-H1975 cells was significantly suppressed by APG and APG+OMT. The mRNA and protein expression of PLOD2 was significantly inhibited by APG and APG+OMT. In addition, APG and OMT had strong binding activity with PLOD2 and EGFR. In APG and APG+OMT groups, the expression of EGFR and proteins in its downstream signaling pathways was significantly down-regulated. It is concluded that APG in combination with OMT could inhibit non-small lung cancer, and the mechanism may be related to EGFR and its downstream signaling pathways. This study lays a new theoretical basis for the clinical treatment of non-small cell lung cancer with APG in combination with OMT and provides a reference for further research on the anti-tumor mechanism of APG in combination with OMT.

[Anti-inflammatory material basis and mechanism of Artemisia stolonifera based on UPLC-Q-TOF-MS combined with network pharmacology and molecular docking].

This study aimed to explore the anti-inflammatory material basis and molecular mechanism of Artemisia stolonifera based on the analysis of the chemical components in different extracted fractions of A. stolonifera and their antioxidant and anti-inflammatory effects in combination with network pharmacology and molecular docking. Thirty-two chemical components were identified from A. stolonifera by ultra-performance liquid chromatography coupled to tandem quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS). Among them, there were 7, 21 and 22 compounds in water, n-butanol and ethyl acetate fractions, respectively. The antio-xidant capacity of different extracted fractions was evaluated by measuring their scavenging ability against 1,1-diphenyl-2-picrylhydrazyl radical 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl(DPPH) and 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulphonic acid)(ABTS) free radicals and total antioxidant capacity [ferric reducing antioxidant power(FRAP) assay]. The inflammatory model of RAW264.7 cells was induced by lipopolysaccharide(LPS), and the levels of nitrite oxide(NO), tumor necrosis factor-α(TNF-α), interleukin-6(IL-6) in the supernatant and the mRNA expression of related inflammatory factors in cells were used to evaluate the anti-inflammatory effects. The results revealed that ethyl acetate fraction of A. stolonifera was the optimal antioxidant and anti-inflammatory fraction. By network pharmacology, it was found that flavonoids such as rhamnazin, eupatilin, jaceosidin, luteolin and nepetin could act on key targets such as TNF, serine/threonine protein kinase 1(AKT1), tumor protein p53(TP53), caspase-3(CASP3) and epidermal growth factor receptor(EGFR), and regulate the phosphatidylinositol-3-kinase-protein kinase B(PI3K-AKT) and mitogen-activated protein kinase(MAPK) signaling pathways to exert the anti-inflammatory effects. Molecular docking further indicated excellent binding properties between the above core components and core targets. This study preliminarily clarified the anti-inflammatory material basis and mechanism of ethyl acetate fraction of A. stolonifera, providing a basis for the follow-up clinical application of A. stolonifera and drug development.

[Comparison of growth and quality of wild and cultivated Artemisia stolonifera].

This paper aims to compare the difference of growth and quality between wild and cultivated Artemisia stolonifera, thereby providing references for further development and utilization of A. stolonifera. The wild and cultivated A. stolonifera from different altitudes were collected, and the agronomic characters, moxa yield, volatile components, flavonoids, and phenolic acids were determined. The results showed that the cultivated species were taller and stronger, with more leaves and branches, than the wild species. The moxa yield and combustion quality of wild products were higher than those of cultivated products. The content of main volatile components in cultivated products was higher than that in wild products. The content of flavonoids and phenolic acids in wild products was higher than that in cultivated products. At high altitude, the ignition performance, combustion persistence, comprehensive combustion performance, and heat release during combustion of the wild and cultivated A. stolonifera. were optimal. At middle altitude, the content of main characteristic volatile components and flavone phenolic acids in the leaves of the cultivated and wild A. stolonifera were the highest. At low altitude, the combustion quality and the content of the above components of the cultivated A. stolonifera decrease significantly. Considering the combustion quality and the content of the internal components of the leaf lint, the middle and high altitude areas are suitable for the artificial cultivation of A. stolonifera.

Genome sequencing reveals chromosome fusion and extensive expansion of genes related to secondary metabolism in Artemisia argyi.

Artemisia argyi, as famous as Artemisia annua, is a medicinal plant with huge economic value in the genus of Artemisia and has been widely used in the world for about 3000 years. However, a lack of the reference genome severely hinders the understanding of genetic basis for the active ingredient synthesis of A. argyi. Here, we firstly report a complex chromosome-level genome assembly of A. argyi with a large size of 8.03 Gb, with features of high heterozygosity (2.36%), high repetitive sequences (73.59%) and a huge number of protein-coding genes (279 294 in total). The assembly reveals at least three rounds of whole-genome duplication (WGD) events, including a recent WGD event in the A. argyi genome, and a recent burst of transposable element, which may contribute to its large genome size. The genomic data and karyotype analyses confirmed that A. argyi is an allotetraploid with 34 chromosomes. Intragenome synteny analysis revealed that chromosomes fusion event occurred in the A. argyi genome, which elucidates the changes in basic chromosome numbers in Artemisia genus. Significant expansion of genes related to photosynthesis, DNA replication, stress responses and secondary metabolism were identified in A. argyi, explaining the extensive environmental adaptability and rapid growth characteristics. In addition, we analysed genes involved in the biosynthesis pathways of flavonoids and terpenoids, and found that extensive gene amplification and tandem duplication contributed to the high contents of metabolites in A. argyi. Overall, the reference genome assembly provides scientific support for evolutionary biology, functional genomics and breeding in A. argyi and other Artemisia species.

Opportunities and challenges of patient-derived models in cancer research: patient-derived xenografts, patient-derived organoid and patient-derived cells.

BACKGROUND: As reported, preclinical animal models differ greatly from the human body. The evaluation model may be the colossal obstacle for scientific research and anticancer drug development. Therefore, it is essential to propose efficient evaluation systems similar to clinical practice for cancer research. MAIN BODY: While it has emerged for decades, the development of patient-derived xenografts, patient-derived organoid and patient-derived cell used to be limited. As the requirements for anticancer drug evaluation increases, patient-derived models developed rapidly recently, which is widely applied in basic research, drug development, and clinical application and achieved remarkable progress. However, there still lack systematic comparison and summarize reports for patient-derived models. In the current review, the development, applications, strengths, and challenges of patient-derived models in cancer research were characterized. CONCLUSION: Patient-derived models are an indispensable approach for cancer research and human health.

Phytochemical Composition and Anti-Aging Activity of Butanol Extract of Hedyotis diffusa in Caenorhabditis elegans.

Hedyotis diffusa Willd. (H. diffusa), a kind of traditional Chinese medicine, has been evaluated to potential display antioxidant and anti-aging effects in vitro experiments. In this work, we investigated the effects on lifespan and stress resistance of the butanol extract from H. diffusa (NHD) in vivo using a Caenorhabditis elegans (C. elegans) model. The phytochemicals of NHD were identified by UPLC-ESI-qTOF-MS/MS method. NHD-treated wild-type N2 worms showed an increase in survival time under both normal and stress conditions. Meanwhile, NHD promoted the healthspan of nematodes by stimulating growth and development, reducing the deposition of age pigment, increasing the activities of superoxide dismutase (SOD) and glutathione peroxidase dismutase (GSH-Px), and decreasing the level of ROS without impairing fertility. Moreover, the upregulating of the expression of daf-16, gst-4, sod-3, hsp12.6 genes and the downregulating of the expression of daf-2 were involved in the NHD-mediated lifespan extension. Finally, the increasing of the expression of GST-4::GFP in CL2166 transgenic nematodes and the life-span-extending activity of NHD was completely abolished in daf-2 and daf-16 mutants further revealed that the potential roles for these genes in NHD-induced longevity in C. elegans. Collectively, our findings suggest that NHD may have an active effect in healthy aging and age-related diseases.

Comparison of Chemical Constituents and Pharmacological Effects of Different Varieties of Chrysanthemum Flos in China.

Chrysanthemum Flos is the prestigious traditional Chinese medicinal material and the popular health drink. This article comprehensively evaluated the chemical constituents, antioxidant activity, and hepatoprotective effects of 25 common chrysanthemum varieties in China. Firstly, we analyzed the chemical compositions of water extracts of chrysanthemum using UPLC/Q-TOF-MS, and identified 29 chemical components. The results displayed that chrysanthemum was rich in chemical constituents, but there were significant differences in the contents of four phenolic acids and five flavonoids among different varieties, and the coefficient of variation (CVs) ranged from 35.96 % to 114.62 %. Then, the antioxidant activities of different chrysanthemums were investigated, respectively via 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azinobis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), and Ferric Reducing Antioxidant Power (FRAP) assays. The spectrum-effect relationships between nine main components and antioxidant activities were investigated to identify the antioxidant constitutes in chrysanthemums. Meanwhile, H2 O2 -induced hepatocyte injury testing showed wide variation in cultivar antioxidant capacity, with Tongchengju (TCJ) producing the best effect (90.32 %), followed by Chuju (CJ; 85.78 %). In addition, the hepatoprotective effects of 8 mainstream varieties were determined by the model of acute alcoholic liver injury. They protected liver from injury by affecting relevant liver function and antioxidant indexes. Huangshangongju (HSG) could decrease aspartate aminotransferase (AST) activity by 39.27 % in liver tissue; Hangju-Fubaiju (HJ-FBJ), Jinsihuangju (JSH), and Chuju (CJ) significantly decreased the malondialdehyde (MDA) content of liver tissue, which reduced by more than 40 %; Jinsihuangju (JSH) of used for tea could double the content of glutathione (GSH) and had the similar effect on superoxide dismutase (SOD) as the positive group, showing significant antioxidant capacity. Therefore, this study confirmed that chrysanthemums are potential resources as antioxidants, functional foods, and medicinal materials. Importantly, it may provide a scientific support for further development and utilization of chrysanthemum, and screen excellent varieties for different demands.

[Effect of different drying methods on drying characteristics, appearance and active components of Belamcandae Rhizoma].

In order to explore the effect of different drying methods(drying-in-the-shade, sun-drying, and hot air drying) on appearance characteristics, internal structure and composition of Belamcandae Rhizoma, so as to provide a theoretical basis for screening out suitable drying methods for primary processing. In this study, the Belamcandae Rhizoma's dynamic changes of the moisture content ratio and drying rate with different drying time under different drying methods, as well as the effects of different drying methods on the appearance, drying rate, density, ash, extractives and the contents of six flavonoids(mangiferin, tectoridin, iridin, tectorigenin, irigenin, irisflorentin) were compared. The results showed that fresh Belamcandae Rhizoma consumed the longest time to reach the water balance point by traditional dry drying in the shade, whiche was about 311 h; that by sun drying was 19.3%, which was shorter than drying in the shade; both drying curves were smoother. The section color of the sun drying samples was the closest to that of fresh samples, but the interior is full of holes, with a low density and loose structure. Hot air drying(40, 60, 80 ℃) could save about 27% to 88% of the drying time, which was greatly shorter, with less pores, a larger density and compact structure. Compared with the traditional drying method, the drying rate of hot air drying was reduced by 13.7%. Ash was affected by temperature, the drying conditions under 40 ℃ and below were not significantly different from those of conventional drying. The ash content decreased by 7.73% to 18.5% compared with conventional drying at 60,80 ℃. After conventional drying and 40 ℃ hot air drying, the contents of tectoridin and iridin(glycosides) in the samples were significantly higher than those in 60,80 ℃ hot air drying, while the contents of tectorigenin, irigenin and irisflorentin(aglycones) dried at 60 ℃ were the best. Therefore, considering comprehensive appearance characteristics and content of medicinal ingredients, traditional Chinese medicinal materials after 60 ℃ hot air drying show a solid texture, tight internal structure, good appearance, appropriate reduction of toxic parasides and higher aglycone content.

[Active fractions of Camellia nitidissima inhibit non-small cell lung cancer via suppressing epidermal growth factor receptor].

The present study explored the effects and its underlying mechanisms of four active fractions of Camellia nitidissima(leaf polyphenols, leaf saponins, flower polyphenols, and flower saponins in C. nitidissima) in inhibiting the proliferation and migration of non-small cell lung cancer(NSCLC) by suppressing the epidermal growth factor receptor(EGFR). MTT assay was used to detect the effect of four active fractions on the proliferation of NCI-H1975 and HCC827 cells. Wound healing assay and Transwell assay were adopted to evaluate the effect of four active fractions on the migration of NSCLC. The effect of four active fractions on the enzyme activity of EGFR was detected. Molecular docking was carried out to explore the direct action capacity and action sites between representative components of the four active fractions and EGPR. Western blot assay was employed to investigate the effect of four active fractions on the protein expression in EGFR downstream signaling pathways. The results of the MTT assay indicated that the cell viability of NCI-H1975 and HCC827 cells was significantly inhibited by four active fractions at 50, 100, 150, and 200 µg·mL~(-1) in a dose-dependent manner. Wound healing assay and Transwell assay revealed that the migration of NCI-H1975 and HCC827 cells was significantly suppressed by four active fractions. In addition, the results of the protein activity assay showed that the enzyme activity of EGFR was significantly inhibited by four active fractions. The molecular docking results confirmed that various components in four active fractions possessed strong binding activity to EGFR enzymes. Western blot assay revealed that four active fractions down-regulated the protein expression of EGFR and its downstream signaling pathways. It is concluded that the four active fractions of C. nitidissima can inhibit NSCLC. The mechanism may be related to EGFR and its downstream signaling pathways. This study provides a new scientific basis for the clinical treatment of NSCLC with active fractions of C. nitidissima, which is of reference significance for further research on the anti-tumor mechanism of C. nitidissima.

Sepiapterin reductase: Characteristics and role in diseases.

Sepiapterin reductase, a homodimer composed of two subunits, plays an important role in the biosynthesis of tetrahydrobiopterin. Furthermore, sepiapterin reductase exhibits a wide distribution in different tissues and is associated with many diseases, including brain dysfunction, chronic pain, cardiovascular disease and cancer. With regard to drugs targeting sepiapterin reductase, many compounds have been identified and provide potential methods to treat various diseases. However, the underlying mechanism of sepiapterin reductase in many biological processes is unclear. Therefore, this article summarized the structure, distribution and function of sepiapterin reductase, as well as the relationship between sepiapterin reductase and different diseases, with the aim of finding evidence to guide further studies on the molecular mechanisms and the potential clinical value of sepiapterin reductase. In particular, the different effects induced by the depletion of sepiapterin reductase or the inhibition of the enzyme suggest that the non-enzymatic activity of sepiapterin reductase could function in certain biological processes, which also provides a possible direction for sepiapterin reductase research.

Isatin dimers and their biological activities.

Dimerization is a promising strategy to develop novel drug candidates that could extend the biological spectrum, enhance the activity, overcome drug resistance, as well as improve pharmacological, pharmacokinetic, and physicochemical profiles. Isatin dimers possess a broad spectrum of biological properties and the isatin dimer indirubin has already been used in the clinic, revealing the potential of isatin dimers as putative drugs. This review covers the recent advances of isatin dimers as pharmacologically significant scaffolds and the structure-activity relationship to set up the direction for the design and development of isatin dimers with higher efficiency and lower toxicity.

[Study on effects of different habitat processing methods of Salviae Miltiorrhizae Radix et Rhizoma in rats with acute myocardial ischemia].

To investigate the effects of different habitat processing methods of Salviae Miltiorrhizae Radix et Rhizoma on acute myocardial ischemia induced by pituitrin in rats. In this experiment, the tail vein injection of pituitrin was used to induce acute myocardial ischemia in rats. Electrocardiograph(ECG) heart rate and ΔST changes were recorded, and the levels of creatine kinase isoenzyme(CK-MB), lactate dehydrogenase(LDH), superoxide dismutase(SOD) and malondialdehyde(MDA) in serum of rats were detected to comprehensively evaluate the effects of six processing methods of Salviae Miltiorrhizae Radix et Rhizoma on serum biochemical indexes of rats with acute myocardial injury. The ECG results showed that the Salviae Miltiorrhizae Radix et Rhizoma dried in a drying oven had a good effect on the improvement of heart rate and ΔST of electrocardiogram after ischemia, and all the other groups had some protective effects to different degrees. The results of biochemical indexes in serum of each group after ischemia showed that the activity of CK-MB decreased most significantly in Salviae Miltiorrhizae Radix et Rhizoma high-dose group with drying in a drying oven after sweating and losing weight in a drying oven, high-dose group with drying in the shade and low-dose group with drying in the shade. The activity of LDH decreased most significantly in Salviae Miltiorrhizae Radix et Rhizoma high-dose group with drying in the shade and low-dose group of drying in the shade. The activity of SOD increased most significantly in Salviae Miltiorrhizae Radix et Rhizoma low-dose group with drying in sun, low-dose group with drying in sun after sweating and losing weight in sun, and low-dose group with drying in a drying oven. The activity of MDA decreased most significantly in Salviae Miltiorrhizae Radix et Rhizoma low-dose group with drying in sun. The comprehensive scoring results showed that the highest score was obtained in Salviae Miltiorrhizae Radix et Rhizoma high-dose group with drying in the shade while the scores of other treatment groups were higher than that of the model group. It could be seen that the Salviae Miltiorrhizae Radix et Rhizoma dried in a drying oven had a good improvement effect on electrocardiograph indexes after acute myocardial injury, the Salviae Miltiorrhizae Radix et Rhizoma dried in the shade had a good improvement effect on serum myocardial enzymes after acute myocardial injury, and the other processing methods had a certain protective effect on myocardial injury. The six processing methods evaluated by pharmacodynamics showed that the Salviae Miltiorrhizae Radix et Rhizoma dried in the shade and dried in a drying oven had good efficacy.

Synergistic combination of DT-13 and Topotecan inhibits aerobic glycolysis in human gastric carcinoma BGC-823 cells via NM IIA/EGFR/HK II axis.

DT-13 combined with topotecan (TPT) showed stronger antitumour effects in mice subcutaneous xenograft model compared with their individual effects in our previous research. Here, we further observed the synergistically effect in mice orthotopic xenograft model. Metabolomics analysis showed DT-13 combined with TPT alleviated metabolic disorders induced by tumour and synergistically inhibited the activity of the aerobic glycolysis-related enzymes in vivo and in vitro. Mechanistic studies revealed that the combination treatment promoted epidermal growth factor receptor (EGFR) degradation through non-muscle myosin IIA (NM IIA)-induced endocytosis of EGFR, further inhibited the activity of hexokinase II (HK II), and eventually promoted the aerobic glycolysis inhibition activity more efficiently compared with TPT or DT-13 monotherapy. The combination therapy also inhibited the specific binding of HK II to mitochondria. When using the NM II inhibitor (-)002Dblebbistatin or MYH-9 shRNA, the synergistic inhibition effect of DT-13 and TPT on aerobic glycolysis was eliminated in BGC-823 cells. Immunohistochemical analysis revealed selective up-regulation of NM IIA while specific down-regulation of p-CREB, EGFR, and HK II by the combination therapy. Collectively, these findings suggested that this regimen has significant clinical implications, warranted further investigation.

Tumor-secreted PAI-1 promotes breast cancer metastasis via the induction of adipocyte-derived collagen remodeling.

BACKGROUND: Breast cancer cells recruit surrounding stromal cells, such as cancer-associated fibroblasts (CAFs), to remodel collagen and promote tumor metastasis. Adipocytes are the most abundant stromal partners in breast tissue, local invasion of breast cancer leads to the proximity of cancer cells and adipocytes, which respond to generate cancer-associated adipocytes (CAAs). These cells exhibit enhanced secretion of extracellular matrix related proteins, including collagens. However, the role of adipocyte-derived collagen on breast cancer progression still remains unclear. METHODS: Adipocytes were cocultured with breast cancer cells for 3D collagen invasion and collagen organization exploration. Breast cancer cells and adipose tissue co- implanted mouse model, clinical breast cancer samples analysis were used to study the crosstalk between adipose and breast cancer cells in vivo. A combination of proteomics, enzyme-linked immunosorbent assay, loss of function assay, qPCR, western blot, database analysis and chromatin immunoprecipitation assays were performed to study the mechanism mediated the activation of PLOD2 in adipocytes. RESULTS: It was found that CAAs remodeled collagen alignment during crosstalk with breast cancer cells in vitro and in vivo, which further promoted breast cancer metastasis. Tumor-derived PAI-1 was required to activate the expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) in CAAs. Pharmacologic blockade of PAI-1 or PLOD2 disrupted the collagen reorganization in CAAs. Mechanistically, it was observed that PI3K/AKT pathway was activated in adipocytes upon co-culturing with breast cancer cells or treatment with recombinant PAI-1, which could promote the translocation of transcription factor FOXP1 into the nucleus and further enhanced the promoter activity of PLOD2 in CAAs. In addition, collagen reorganization at the tumor-adipose periphery, as well as the positive relevance between PAI-1 and PLOD2 in invasive breast carcinoma were confirmed in clinical specimens of breast cancer. CONCLUSION: In summary, our findings revealed a new stromal collagen network that favors tumor invasion and metastasis establish between breast cancer cells and surrounding adipocytes at the tumor invasive front, and identified PLOD2 as a therapeutic target for metastatic breast cancer treatment.

[Study on scavenging activity to DPPH free radical of different polarity components in Guizhou Miao medicine "bod zangd dak"].

The paper is aimed to search more natural plant antioxidants and further research and develop new medicinal plant resources in Guizhou. The Guizhou special miao medicine "bod zangd dak" was extracted with 60% ethanol. The antioxidant activity of the different polarity components separated from the extract was tested by DPPH method with ascorbic acid as positive control. The results showed that the IC50 of the different polarity components was as following: ascorbic acid (0.033 4 g x L(-1)) < ethyl acetate components (0.052 3 g x L(-1)) < total tannins components (0.054 9 g x L(-1)) < 60% ethanol extraction components (0.076 7 g x L(-1)) < butanol extraction components (0.110 g x L(-1)) < water-soluble polysaccharides components (0.168 g x L(-1)) < water extraction components (0.174 g x L(-1)) < water components after extraction (0.226 g x L(-1)) < total polysaccharides components (0.645 g x L(-1)). It is concluded that the different polarity components have different free radical scavenging activity and that provides a scientific basis for further search of the active ingredients and the activive mechanism.

[UPLC and HPLC analysis on contents of astilbin and engeletin in dong medicine "sunl gaems" of Guizhou origin by QAMS].

This study aimed to simultaneously determine the contents of astilbin and engeletin in dong medicine "sunl gaems" of Guizhou origin by quantitative analysis of multi-components by single marker (QAMS), with astilbin as the internal standard substance. On UPLC and HPLC chromatograms, different models of instruments were used to investigate relative correction factors (RCF), in order to discuss the interoperability of RCFs established in different chromatographic systems. The engeletin content was calculated based on the established RCFs and compared by the one point external standard method and the external standard working curve method, in order to verify the accuracy of QAMS. According to the result, in different chromatograms, the ratios between RCF and retention time of engeletin and astilbin had a good reproducibility, with RSD between 2.0% and 1.8%, both were less than 3%. The relative differences among results of QAMS, the external standard working curve method of dong medicine "sunl gaems" ranged between 1.6% and 3.9%, with RSD between 2.02%-0.80% in line with relevant requirements and Pearson correlation coefficient at 0.9998 (P <0.01). The findings showed that QAMS was an accurate, reliable and highly reproducible method to determine the contents of astilbin and engeletin in dong medicine "sunl gaems" of Guizhou origin and so could be used to control the inherent quality of the herb.

Influence of Gut Microbiota-Mediated Immune Regulation on Response to Chemotherapy.

The involvement of the gut microbiota in anti-cancer treatment has gained increasing attention. Alterations to the structure and function of the gut bacteria are important factors in the development of cancer as well as the efficacy of chemotherapy. Recent studies have confirmed that the gut microbiota and related metabolites influence the pharmacological activity of chemotherapeutic agents through interactions with the immune system. This review aims to summarize the current knowledge of how malignant tumor and chemotherapy affect the gut microbiota, how the gut microbiota regulates host immune response, and how interactions between the gut microbiota and host immune response influence the efficacy of chemotherapy. Recent advances in strategies for increasing the efficiency of chemotherapy based on the gut microbiota are also described. Deciphering the complex homeostasis maintained by the gut microbiota and host immunity provides a solid scientific basis for bacterial intervention in chemotherapy.