Natural alkaloids from Dicranostigma leptopodum (Maxim.) Fedde and their G5. NHAc-PBA dendrimer-alkaloid complexes for targeting chemotherapy in breast cancer MCF-7 cells.

Herein, we isolated five natural alkaloids, iso-corydine (iso-CORY), corydine (CORY), sanguinarine (SAN), chelerythrine (CHE) and magnoflorine (MAG), from traditional medicinal herb Dicranostigma leptopodum (Maxim.) Fedde (whole herb) and elucidated their structures. Then we synthesised G5. NHAc-PBA as targeting dendrimer platform to encapsulate the alkaloids into G5. NHAc-PBA-alkaloid complexes, which demonstrated alkaloid-dependent positive zeta potential and hydrodynamic particle size. G5. NHAc-PBA-alkaloid complexes demonstrated obvious breast cancer MCF-7 cell targeting effect. Among the G5. NHAc-PBA-alkaloid complexes, G5.NHAc-PBA-CHE (IC50=13.66 µM) demonstrated the highest MCF-7 cell inhibition capability and G5.NHAc-PBA-MAG (IC50=24.63 µM) had equivalent inhibitory effects on cell proliferation that comparable to the level of free MAG (IC50=23.74 µM), which made them the potential breast cancer targeting formulation for chemotherapeutic application. This work successfully demonstrated a pharmaceutical research model of 'natural bioactive product isolation-drug formulation preparation-breast cancer cell targeting inhibition'.

Quality Evaluation of Peony Petals Based on the Chromatographic Fingerprints and Simultaneous Determination of Sixteen Bioactive Constituents Using UPLC-DAD-MS/MS.

In this study, a validated quality evaluation method with peony flower fingerprint chromatogram combined with simultaneous determination of sixteen bioactive constituents was established using UPLC-DAD-MS/MS. The results demonstrated that the method was stable, reliable, and accurate. The UPLC chemical fingerprints of 12 different varieties of peonies were established and comprehensively evaluated by similarity evaluation (SE), hierarchical cluster analysis (HCA), principal component analysis (PCA), and quantification analysis. The results of SE indicated that similar chemical components were present in these samples regardless of variety, but there were significant differences in the content of chemical components and material basis characteristics. The results of HCA and PCA showed that 12 varieties of samples were divided into two groups. Four flavonoids (11, 12, 13, and 16), five monoterpenes and their glycosides (3, 4, 6, 14, and 15), three tannins (7, 9, and 10), three phenolic acids (1, 2, and 5), and one aromatic acid (8) were identified from sixteen common peaks by standards and liquid chromatography-mass spectrometry (LC-MS). The simultaneous quantification of six types of components was conducted with the 12 samples, it was found that the sum contents of analytes varied obviously for peony flower samples from different varieties. The content of flavonoids, tannins, and monoterpenes (≥19.34 mg/g) was the highest, accounting for more than 78.45% of the total compounds. The results showed that the flavonoids, tannins, and monoterpenes were considered to be the key indexes in the classification and quality assessment of peony flower. The UPLC-DAD-MS/MS method coupled with multiple compounds determination and fingerprint analysis can be effectively applied as a feature distinguishing method to evaluate the compounds in peony flower raw material for product quality assurance in the food, pharmaceutical, and cosmetic industries. Moreover, this study provides ideas for future research and the improvement of products by these industries.

Natural phytoalexins inspired the discovery of new biphenyls as potent antifungal agents for treatment of invasive fungal infections.

With the aim of discovering novel and effective antifungal agents derived from natural sources, a series of new biphenyls based on natural biphenyl phytoalexins were designed, synthesized and evaluated for their antifungal activities against four invasive fungi. By modifying the two benzene rings of noraucuparin, a well-known biphenyl phytoantitoxin, some promising compounds with remarkable antifungal activity were discovered. Notably, compounds 23a, 23e and 23h exhibited potent activities and a broad antifungal spectrum with low MICs of 0.25-16 µg/mL, which were 8-256-fold more potent than that of the lead compound noraucuparin. Particularly, they displayed comparable potency to the positive control amphotericin B against Cryptococcus neoformans. Some interesting structure-activity relationships have also been discussed. Preliminary mechanism studies revealed that compound 23h might achieve its rapid fungicidal activity by disrupting the fungal cell membrane. Moreover, compound 23h exhibited significant inhibition against some virulence factors of Cryptococcus neoformans, low toxicity to normal human cells, as well as favorable pharmacokinetic and drug-like properties. The above results evidenced that the development of new antifungal candidates derived from natural phytoalexins was a bright and promising strategy.

Qualitative and quantitative analysis of polyphenols in camelina seed and theirs antioxidant activities.

Camelina [Camelina sativa (L.) Crantz] seed has long been consumed as a source of food in Canada. But limited information is available concerning the systematical evaluation of the composition, content, and antioxidant activity of Camelina seed polyphenol extract (CSPE). Therefore, the aim of this study was to identify, quantify and evaluate the antioxidant activity of CSPE. The result showed that eight compositions were identified and determined by the UPLC-DAD-ESI-MS2 analysis. CSPE has potent free radical scavenging capacity. CSPE treatment significantly increased the activities of the antioxidant enzymes (superoxide dismutase and catalase) and glutathione content in a dose-dependent manner in RAW264.7 cells with oxidative injury and also reduced malondialdehyde content (P < 0.01). It may be concluded that CSPE has a strong antioxidant activity as depicted by the in vitro experiments and thus possesses the potential to be developed as food antioxidants or as an ingredient in functional foods.

Deciphering the pharmacological mechanisms of Chaenomeles Fructus against rheumatoid arthritis by integrating network pharmacology and experimental validation.

Chaenomeles Fructus is a plant that can be used for both food and medicine. Modern studies have shown that Chaenomeles Fructus has anti-inflammatory and immunosuppressive effects on arthritis. However, the mechanism of action of Chaenomeles Fructus on rheumatoid arthritis (RA) and its main active ingredients are still unclear. This study was aimed at devising an integrated strategy for investigating the bioactivity constituents and possible pharmacological mechanisms of Chaenomeles Fructus against RA. The components of Chaenomeles Fructus were analyzed using UPLC-Q-Exactive orbitrap MS techniques and applied to screen the active components of Chaenomeles Fructus according to their oral bioavailability and drug-likeness index. Then, we speculated on the potential molecular mechanisms of Chaenomeles Fructus against RA through a network pharmacology analysis. Finally, the potential molecular mechanisms of Chaenomeles Fructus against RA were validated in a complete Freund's adjuvant (CFA)-induced RA rat model. We identified 48 components in Chaenomeles Fructus and screened seven bioactive ingredients. The results of the network pharmacology prediction and the experimental verification results were analyzed by Venn analysis, and the experimental results concluded that Chaenomeles Fructus mainly interferes with the inflammation of RA by inhibiting arachidonic acid metabolism and the MAPK signaling pathway. This study identified the ingredients of Chaenomeles Fructus by UPLC-Q-Exactive orbitrap MS and explained the possible mechanisms of Chaenomeles Fructus against RA by integrating network pharmacology and experimental validation.

The Complete Chloroplast Genome Sequence of Eupatorium fortunei: Genome Organization and Comparison with Related Species.

Eupatorium fortunei Turcz, a perennial herb of the Asteraceae family, is one of the horticultural and medicinal plants used for curing various diseases and is widely distributed in China and other Asian countries. It possesses antibacterial, antimetastatic, antiangiogenic, and antioxidant properties along with anticancer potential. However, the intrageneric classification and phylogenetic relationships within Eupatorium have long been controversial due to the lack of high-resolution molecular markers, and the complete chloroplast (cp) genome sequencing has not been reported with new evolutionary insights. In the present study, E. fortunei was used as an experimental material, and its genome was sequenced using high-throughput sequencing technology. We assembled the complete cp genome, and a systematic analysis was conducted for E. fortunei, acquiring the correspondence of its NCBI accession number (OK545755). The results showed that the cp genome of E. fortunei is a typical tetrad structure with a total length of 152,401 bp, and the genome encodes 133 genes. Analysis of the complete cp genomes of 20 Eupatorieae shows that the number of simple sequence repeats (SSRs) ranged from 19 to 36 while the number of long sequence repeats was 50 in all cases. Eleven highly divergent regions were identified and are potentially useful for the DNA barcoding of Eupatorieae. Phylogenetic analysis among 22 species based on protein-coding genes strongly supported that E. fortunei is more closely related to Praxelis clematidea and belongs to the same branch. The genome assembly and analysis of the cp genome of E. fortunei will facilitate the identification, taxonomy, and utilization of E. fortunei as well as provide more accurate evidence for the taxonomic identification and localization of Asteraceae plants.

Safflower extract improves depression in mice by inhibiting the TLR4-NLRP3 inflammation signaling pathway.

BACKGROUND: Safflower extract (SE) improves depression in mice by inhibiting the TLR4-NLRP3 inflammatory signaling pathway. METHODS: Chronic unpredictable mild stress (CUMS) was used to establish a mouse model of depression. A total of 60 adult male ICR mice were randomly divided into 6 groups: control group, depression group (CUMS only), SE (10 mg/kg) + depression group (CUMS+SE, 10 mg/kg), SE (30 mg/kg) + depression group (CUMS+SE, 30 mg/kg), Cli-095 + depression group (CUMS+Cli-95), and fluoxetine hydrochloride (FLU) + depression group (CUMS+FLU). We assessed the depressive behaviors of these mice using the sucrose preference test (SPT), the open field test (OFT), the forced swim test (FST), and the tail suspension test (TST). We measured the expression levels of SOD, MDA, GSH-Px, 5-HT, NE, TNF-α, IL-1ß, and IL-6 using ELISA kits. Western blot was used to determine the relative expression levels of TLR4, p38, NF-κB, NLRP3, and caspase-1. RESULTS: SE significantly improved the results of the SPT, OFT, FST, and TST. SE also increased the expression levels of 5-HT and NE in the prefrontal cortex while decreased the expression levels of TNF-α, IL-1ß, and IL-6 compared with CUMS. SE (10 or 30 mg/kg) or FLU (10 mg/kg) significantly inhibited the expression of TLR4 and p-p38 induced by CUMS. SE significantly inhibited the expression of p-NF-κB in the prefrontal cortex and hippocampus induced by CUMS. The decrease of NLRP3 and caspase-1 were obviously reversed after administration of SE (10 or 30 mg/kg) or FLU (10 mg/kg). CONCLUSIONS: The results showed that SE has potential antidepressant effects in CUMS mice, and its underlying mechanism may be related to its effects on inflammation and the TLR4-NF-κB-NLRP3 signaling pathway in the brain.

Hepatic targeting of glycyrrhetinic acid via nanomicelles based on stearic acid-modified fenugreek gum.

This study aimed to increase the solubility of glycyrrhetinic acid (GA) in water and enhance its liver-targeting ability using self-assembling nanomicelles (NMs) based on stearic acid-modified fenugreek gum (FG-C18). The GA/FG-C18 NMs were prepared by an ultrasonication dispersion method. The nanomicelles were spherical particles with a particle size of 198.61 ± 1.58 nm and a zeta potential of -30.12 ± 0.28 mV. The drug loading and encapsulation efficiency were 13.34 ± 0.24% and 80.07 ± 1.44%, respectively. The results of differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD) indicated that GA was successfully encapsulated into the nanomicelles in a molecularly dispersed state. An in vitro release test showed that GA/FG-C18 NMs possessed a slow drug release profile in PBS (pH 7.4) over 200 h. The cytotoxicity assay indicated that GA/FG-C18 NMs showed much higher inhibitory efficacy in HepG2 cells than in MCF-7 cells. Tissue section studies indicated that the accumulation of DiR-loaded FG-C18 nanomicelles in the liver of mice was higher than that of the DiR solution, and the fluorescence intensity decreased over time. GA/FG-C18 NMs showed a larger area under the curve (AUC) and mean residence time (MRT) compared with free GA after intravenous administration in mice. The in vivo studies showed that GA mainly accumulated in the liver after encapsulation by FG-C18 NMs, and the drug concentration was higher than that of free GA. These results suggested that FG-C18 NMs could serve as a potential drug delivery system for targeting GA to liver tissue.

The MRVI1-AS1/ATF3 signaling loop sensitizes nasopharyngeal cancer cells to paclitaxel by regulating the Hippo-TAZ pathway.

Long non-coding RNA (lncRNA) plays an important role in malignant tumor occurrence, development, and chemoresistance, but the mechanism of how they affect nasopharyngeal cancer (NPC) paclitaxel chemosensitivity is unclear. In this study, lncRNA array of CNE-1 and HNE-2 paclitaxel-resistant cells and their parental strains revealed that the paclitaxel-resistant strains had significantly lower MRVI1-AS1 (murine retrovirus integration site 1 homolog antisense RNA 1) expression than the parental strains, and that MRVI1-AS1 overexpression in vitro and in vivo increased paclitaxel chemosensitivity. Further, MRVI1-AS1 upregulated ATF3 (activating transcription factor 3) by simultaneously inhibiting miR-513a-5p (microRNA-513a-5p) and miR-27b-3p expression levels to increase NPC paclitaxel chemosensitivity. Chromatin immunoprecipitation and quantitative real-time PCR showed that ATF3 could feed-back MRVI1-AS1 regulation positively. Furthermore, MRVI1-AS1 and ATF3 could form a positive feedback loop, which promoted the expression of RASSF1 (Ras association domain family member 1), a Hippo-TAZ (tafazzin) signaling pathway regulatory factor, thereby inhibiting TAZ expression. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide) assay and flow cytometry showed that the decreased TAZ increased NPC cell paclitaxel chemosensitivity. Overall, the results indicate that the MRVI1-AS1/ATF3 signaling pathway can increase NPC paclitaxel chemosensitivity by modulating the Hippo-TAZ signaling pathway. Therefore, targeting the loop may be a new NPC treatment strategy.

The advances in research on the pharmacological effects of Fructus Ligustri Lucidi.

Fructus Ligustri Lucidi is a well-known invigorator in Chinese materia medica with hepatoprotective effect, anticancer activity, antioxidant activity, and so on. And oleanolic acids are the major pharmacologically active components in Fructus Ligustri Lucidi. So it has great value in medical health, and may be developed to a complementary and alternative medicine through further research. In this paper, the advances in research on pharmacological effects of Fructus Ligustri Lucidi were summarized by reviewing the recent related literature.

Emodin can induce K562 cells to erythroid differentiation and improve the expression of globin genes.

In China, the traditional Chinese medicine "YiSui ShenXu Granule" has been used for treating ß-thalassemia over 20 years and known to be effective in clinic. Several purified components from "YiSui ShenXu Granule" are tested in K562 cells to reveal its effect on globin expression and erythroid differentiation, and one of the purified components, emodin, was demonstrated to increase the expression of α-, ε-, γ-globin, CD235a, and CD71 in K562 cells. Moreover, the increase of their expression is emodin concentration-dependent. The mRNA and microRNA (miRNA) expression profiles are further analyzed and 417 mRNAs and 35 miRNAs with differential expression between untreated and emodin-treated K562 cells were identified. Among them, two mRNAs that encode known positive regulators of erythropoiesis, ALAS2, and c-KIT respectively, increased during emodin-induced K562 erythroid differentiation, meanwhile, two negative regulators, miR-221 and miR-222, decreased during this process. These results indicate that emodin can improve the expression of globin genes in K562 cells and also induce K562 cells to erythroid differentiation possibly through up-regulating ALAS2 and c-KIT and down-regulating miR-221 and miR-222.

In vitro antifungal activity of sanguinarine and chelerythrine derivatives against phytopathogenic fungi.

In order to understand the antifungal activity of some derivatives of sanguinarine (S) and chelerythrine (C) and their structure-activity relationships, sixteen derivatives of S and C were prepared and evaluated for in vitro antifungal activity against seven phytopathogenic fungi by the mycelial growth rate method. The results showed that S, C and their 6-alkoxy dihydro derivatives S1-S4, C1-C4 and 6-cyanodihydro derivatives S5, C5 showed significant antifungal activity at 100 µg/mL against all the tested fungi. For most tested fungi, the median effective concentrations of S, S1, C and C1 were in a range of 14-50 µg/mL. The structure-activity relationship showed that the C=N+ moiety was the determinant for the antifungal activity of S and C. S1-S5 and C1-C5 could be considered as the precursors of S and C, respectively. Thus, the present results strongly suggested that S and C or their derivatives S1-S5 and C1-C5 should be considered as good lead compounds or model molecules to develop new anti-phytopathogenic fungal agents. can't login to work station for 2hrs--took 2 hrs vacation