Garcinone E suppresses breast cancer growth and metastasis by modulating tumor-associated macrophages polarization via STAT6 signaling.

Cancer metastasis remains the most common cause of death in breast cancer patients. Tumor-associated macrophages (TAMs) are a novel therapeutic target for the treatment of metastatic breast cancer. Despite the good anti-cancer activity of garcinone E (GE), there are no reports on its therapeutic effects on breast cancer metastasis. The objective of this study was to examine the anti-cancer effects of GE on metastatic breast cancer. RAW 264.7 and THP-1 cells were polarized to M2 macrophages by IL-4/IL-13 in vitro. A 4T1 mouse breast cancer model and the tail vein breast cancer metastasis model were used to explore the effect of GE on breast cancer growth and metastasis in vivo. In vitro studies showed that GE dose-dependently suppressed IL-4 + IL-13-induced expression of CD206 in both RAW 264.7 cells and differentiated THP-1 macrophages. However, GE did not affect the LPS + IFN-γ-induced polarization to the M1-like macrophages in vitro. GE inhibited the expression of the M2 macrophage specific genes in RAW 264.7 cells, and simultaneously impaired M2 macrophage-induced breast cancer cell proliferation and migration, and angiogenesis. In animal studies, GE significantly suppressed tumor growth, angiogenesis, and lung metastasis in 4T1 tumor-bearing mice, without causing toxicity. In both tumor and lung tissues, the proportion of M2-like TAMs was significantly decreased while the proportion of M1-like TAMs was markedly increased by GE treatment. Mechanistically, GE inhibited phosphorylation of STAT6 in vitro and in vivo. Our results demonstrate for the first time that GE suppresses breast cancer growth and pulmonary metastasis by modulating M2-like macrophage polarization through the STAT6 signaling pathway.

Glycyrrhetinic acid suppresses breast cancer metastasis by inhibiting M2-like macrophage polarization via activating JNK1/2 signaling.

BACKGROUND: Breast cancer metastasis is leading cause of cancer death among women worldwide. Tumor-associated macrophages (TAMs) have been considered as potential targets for treating breast cancer metastasis because they promote tumor growth and development. Glycyrrhetinic acid (GA) is one of the most important phytochemicals of licorice which has shown promising anti-cancer efficacies in pre-clinical trials. However, the regulatory effect of GA on the polarization of TAMs remains elusive. PURPOSE: To investigate the role of GA in regulating the polarization of M2 macrophages and inhibiting breast cancer metastasis, and to further explore its underlying mechanisms of action. STUDY DESIGN: IL-4 / IL-13-treated RAW 264.7 and THP-1 cells were used as the M2-polarized macrophages in vitro. A 4T1 mouse breast cancer model and the tail vein breast cancer metastasis model were applied to study the effect of GA on breast cancer growth and metastasis in vivo. RESULTS: In vitro studies showed that GA significantly inhibited IL-4 / IL 13-induced M2-like polarization in RAW 264.7 and THP-1 macrophages without affecting M1-like polarization. GA strongly decreased the expression of M2 macrophage markers CD206 and Arg-1, and reduced the levels of the pro-angiogenic molecules VEGF, MMP9, MMP2 and IL-10 in M2 macrophages. GA also increased the phosphorylation of JNK1/2 in M2 macrophages. Moreover, GA significantly suppressed M2 macrophage-induced cell proliferation and migration in 4T1 cancer cells and HUVECs. Interestingly, the inhibitory effects of GA on M2 macrophages were abolished by a JNK inhibitor. Animal studies showed that GA significantly suppressed tumor growth, angiogenesis, and lung metastasis in BALB/c mice bearing breast tumor. In tumor tissues, GA reduced the number of M2 macrophages but elevated the proportion of M1 macrophages, accompanied by activation of JNK signaling. Similar results were found in the tail vein breast cancer metastasis model. CONCLUSION: This study demonstrated for the first time that GA could effectively suppress breast cancer growth and metastasis by inhibiting macrophage M2 polarization via activating JNK1/2 signaling. These findings indicate that GA could be served as the lead compound for the future development of anti-breast cancer drug.

Natural compound glycyrrhetinic acid protects against doxorubicin-induced cardiotoxicity by activating the Nrf2/HO-1 signaling pathway.

BACKGROUND: As one of the most classic antineoplastic agents, doxorubicin (Dox) is extensively used to treat a wide range of cancers. Nevertheless, the clinical outcomes of Dox-based therapies are severely hampered due to the significant cardiotoxicity. Glycyrrhetinic acid (GA) is the major biologically active compound of licorice, one of the most well-known food additives and medicinal plants in the world. We previously demonstrated that GA has the potential capability to protect mice from Dox-induced cardiac injuries. However, the underlying cardioprotective mechanism remains unexplored. PURPOSE: To investigate the cardioprotective benefits of GA against Dox-induced cardiotoxicity and to elucidate its mechanisms of action. STUDY DESIGN/METHODS: H9c2 cardiomyoblasts and AC16 cardiomyocytes were used as the cell models in vitro. A transgenic zebrafish model and a 4T1 mouse breast cancer model were applied to explore the cardioprotective effects of GA in vivo. RESULTS: In vitro, GA inhibited Dox-induced cell death and LDH release in H9c2 and AC16 cells without affecting the anti-cancer effects of Dox. GA significantly alleviated Dox-induced ROS generation, mitochondrial dysfunction, and apoptosis in H9c2 cells. Moreover, GA abolished the expression of pro-apoptotic proteins and restored Nrf2/HO-1 signaling pathway in Dox-treated H9c2 cells. On the contrary, Nrf2 knockdown strongly abrogated the cardioprotective effects of GA on Dox-treated H9c2 cells. In vivo, GA attenuated Dox-induced cardiac dysfunction by restoring stroke volume, cardiac output, and fractional shortening in the transgenic zebrafish embryos. In a 4T1 mouse breast cancer model, GA dramatically prevented body weight loss, attenuated cardiac dysfunction, and prolonged survival rate in Dox-treated mice, without compromising Dox's anti-tumor efficacy. Consistently, GA attenuated oxidative injury, reduced cardiomyocytes apoptosis, and restored the expressions of Nrf2 and HO-1 in Dox-treated mouse hearts. CONCLUSION: GA protects against Dox-induced cardiotoxicity by suppressing oxidative stress, mitochondrial dysfunction, and apoptosis via upregulating Nrf2/HO-1 signaling pathway. These findings could provide solid evidence to support the further development of GA as a feasible and safe adjuvant to Dox chemotherapy for overcoming Dox-induced cardiotoxicity.

High Biocompatible Poly(lactic-co-glycolic acid)-Based Nanosensitizer With Magnetic Resonance Imaging Capacity for Tumor Targeted Microwave Hyperthermia and Chemotherapy.

Microwave (MW) hyperthermia has been widely studied in tumor therapy, while the lack of specificity, and the potential toxicity induced by instability or difficulty in degradation of existed MW thermal sensitizers still limits the application. Herein, a new biocompatible Poly(lactic-co-glycolic acid) (PLGA)-based nanosensitizer of Dtxl-Gd@PLGA-PEG-TPP (DGPPT) with capacities of magnetic resonance (MR) imaging and mitochondrial targeting for MW hyperthermia combined with chemotherapy was constructed via a double emulsion solvent evaporation method. The modified TPP significantly enhanced the specificity of sensitizer for targeting mitochondria, a heat-sensitive energy supply plant in cells. Thus the MW thermal damage induced by the loaded Gd in PLGA nanospheres was also strengthened. Together, the system could also achieve MR imaging due to the existence of Gd. In addition, the encapsulated Dtxl performed the chemotherapy of inhibiting mitochondrial function for assisting with MW hyperthermia. In vivo experiments demonstrated that PLGA had high biocompatibility that no obvious damage occurred even the dose was up to 200 mg/kg. Meanwhile, DGPPT+MW representing the combination of mitochondrial targeting and MW hyperthermia-chemotherapy has also been proved to shrink tumor size effectively. This study provides a new direction for building biosafe and multifunctional MW sensitizer with active targeting ability to impede tumor growth.

Lanthanide europium MOF nanocomposite as the theranostic nanoplatform for microwave thermo-chemotherapy and fluorescence imaging.

BACKGROUNDS: Microwave sensitization nanoplatform, integrating multiple functional units for improving tumor selectivity, is of great significance for clinical tumor microwave treatment. Lanthanide europium metal organic framework (EuMOF) is expected to be a theranostic nanoplatform owing to its unique luminescent and microwave sensitization properties. However, it is difficult to be applied to complicated biological systems for EuMOF due to its rapid degradation induced by the solvent molecular and ionic environment. In this work, a luminescent EuMOF nanocomposite (EuMOF@ZIF/AP-PEG, named EZAP) was designed, which brought the multifunctional characteristics of microwave sensitization, fluorescence imaging and drug loading. RESULTS: Lamellar EuMOF was synthesized by a hydrothermal method. Through the charge adsorption mechanism, the zeolite imidazole framework (ZIF) structure was intensively assembled on the surface of EuMOF to realize the protection. Then, through in-situ Apatinib drug loading and PEG modification, EZAP nanocomposite was finally obtained. Apatinib (AP) was a kind of chemotherapy drug approved by Food and Drug Administration for targeted therapy of tumors. PEG modification increased long-term circulation of EZAP nanocomposite. The physical and chemical structure and properties of EuMOF@ZIF (EZ) were systematically represented, indicating the successful synthesis of the nanocomposite. The toxic and side effects were negligible at a safe dose. The growth of human liver cancer cells and murine liver cancer cells in vitro was significantly inhibited, and the combined microwave-thermal therapy and chemotherapy in vivo achieved high anti-cancer efficacy. Moreover, EZAP nanocomposite possessed bright red fluorescence, which can be applied for tumor imaging in tumor-bearing mice in vivo. CONCLUSION: Therefore, EZAP nanocomposite showed high microwave sensitization, excellent fluorescence properties and outstanding drug loading capacity, establishing a promising theranostic nanoplatform for tumor therapy and fluorescence imaging. This work proposes a unique strategy to design for the first time a multifunctional nanoplatform with lanthanide metal organic frameworks for biological applications in tumor therapy and diagnosis.

Graphdiyne nanosheets as a platform for accurate copper(ii) ion detection via click chemistry and fluorescence resonance energy transfer.

A novel sensing platform for sensitive detection of copper(ii) ions (Cu2+) in living cells and body fluids was developed by taking advantage of the excellent fluorescence quenching ability of graphdiyne (GDY) and the high specificity of click chemistry for the first time.

Long-term exposure to phenanthrene at environmental-level induces intestinal dysbiosis and disrupted hepatic lipid metabolism in mice.

Phenanthrene (Phe), among the most ubiquitous polycyclic aromatic hydrocarbons (PAHs) existing in nature and foodstuffs, has severe effects on hepatic lipids metabolism. However, the detailed mechanism involved is still unknown. For environmental chemicals can disturb intestinal microbiota, which plays a vital role in lipids metabolism, we hypothesized that oral exposure to Phe may disrupt the intestinal microbiota, leading to the induction of an abnormal inflammatory response and lipid metabolism dysfunction. Herein, male mice were orally exposed to Phe (0.05, 0.5 and 5 mg/kg/2d) for ten weeks and the results showed that long term exposure to Phe induced significant alteration in relative Bacteroidetes, Firmicutes and Proteobacteria abundance in male mice. Histopathological anomalies, and significantly increased hepatic levels of free fatty acid, cholesterol and triglyceride were observed as well. The expression of hepatic proteins linked to lipid metabolism including peroxisome proliferator-activated receptors (PPARs), liver X receptor ß (LXRß) and retinoid X receptors (RXRs) were upregulated. The importance of the gut microbiota in Phe-altered lipid metabolism disorder was further confirmed by fecal microbiota transplantation (FMT). FMT intervention boosted microbial diversity and attenuated Phe-induced elevation in liver somatic index and hepatic total lipids levels. These results demonstrated that environmental-level Phe altered the composition of gastrointestinal bacteria and subsequently induced hepatic lipid metabolism disorder. These results would be helpful for understanding the health risk posed by Phe.

Topical Application of Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells in Combination with Sponge Spicules for Treatment of Photoaging.

PURPOSE: The topical application of exosomes secreted by mesenchymal stem cells (MSC-Exos) on the skin is a very new and interesting topic in the medical field. In this study, we aimed to investigate whether marine sponge Haliclona sp. spicules (SHSs) could effectively enhance the skin delivery of human umbilical cord-derived MSC-Exos (hucMSC-Exos), and further evaluate the topical application of hucMSC-Exos combined with SHSs in rejuvenating photoaged mouse skin. MATERIALS AND METHODS: SHSs were isolated from the explants of sponge Haliclona sp. with our proprietary method, and hucMSC-Exos were prepared from the conditioned medium of hucMSCs using ultracentrifugation. The effects of SHSs on the skin penetration of fluorescently labeled hucMSC-Exos were determined using confocal microscopy in vitro (porcine skin) and in vivo (mouse skin). The therapeutic effects of hucMSC-Exos coupled with SHSs against UV-induced photoaging in mice were assessed by using microwrinkles analysis, pathohistological examination and real-time RT-PCR. We also tested the skin irritation caused by the combination of hucMSC-Exos and SHSs in guinea pigs. RESULTS: In vitro results showed that hucMSC-Exos could not readily penetrate through porcine skin by themselves. However, SHSs increased the skin absorption of exosomes by a factor of 5.87 through creating microchannels. Similar penetration enhancement of hucMSC-Exos was observed after SHSs treatment in mice. The combined use of hucMSC-Exos and SHSs showed significant anti-photoaging effects in mice, including reducing microwrinkles, alleviating histopathological changes, and promoting the expression of extracellular matrix constituents, whereas hucMSC-Exos alone produced considerably weaker effects. Skin irritation test showed that the combination of hucMSC-Exos and SHSs caused slight irritation, and the skin recovered shortly. CONCLUSION: SHSs provide a safe and effective way to enhance the skin delivery of MSC-Exos. Moreover, the combination of MSC-Exos and SHSs may be of much use in the treatment of photoaging.

Chemical constituents from Lonicera japonica flower buds and their anti-hepatoma and anti-HBV activities.

Three new naturally occurring monoterpenoids, japopenoid A (1), japopenoid B (23) japopenoid C (24), and one new caffeoylquinic acid derivative (28), together with thirty-one known compounds (2-22, 25-27, 29-35), were isolated and identified from the flower buds of Lonicera japonica Thunb. Their structures were determined by extensive 1D and 2D NMR spectroscopic methods, high-resolution mass spectrometry, and the absolute configurations of 1, 23, 24 were determined by comparison of their electronic circular dichroism (ECD) spectrum with literature and theoretical calculation. Structurally, compound 1 is a monoterpenoid featured with an unusual tricyclic skeleton. All compounds (1-35) were evaluated for their cytotoxicities against human liver cancer cell lines (HepG 2 and SMMC-7721). Compound 12 exhibited the most potent activity with IC50 values of 26.54 ±â€¯1.95 and 8.72 ±â€¯1.57 µg/ml against HepG 2 and SMMC-7721, and the IC50 values of compound 13 were 26.54 ±â€¯1.95 and 12.35 ±â€¯1.43 µg/ml, respectively. Western blot results further proved that compound 13 induces hepatoma cell apoptosis via the intrinsic apoptosis pathway. In addition, most terpenoids showed inhibitory activity against HBsAg and HBeAg secretion, and HBV DNA replication. In particular, 25 µg/mlof compound 11 inhibits HBsAg and HBeAg secretion, and HBV DNA replication by 39.39 ±â€¯5.25, 15.64 ±â€¯1.25, and 16.13 ±â€¯4.10% compared to the control (p < 0.05). These results indicated that L. japonica flower buds could be served as functional food for anti-hepatoma and anti-HBV activities.

Study of pro-angiogenic activity of astilbin on human umbilical vein endothelial cells in vitro and zebrafish in vivo.

Astilbin is a dihydroflavonol natural product isolated from a variety of food and medicinal herbs (e.g. Smilax glabra Roxb.), and its mechanism of action in vascular pharmacology remains unclear. The aim of this study was to investigate the pro-angiogenic effects of astilbin and its putative mechanism of action. Briefly, our in vitro studies showed a dose-dependent ability of astilbin to increase the ability of HUVECs to proliferate and migrate, and undergo cell invasion and tube formation. Moreover, astilbin significantly increased the expression levels of several major proteins involved in the angiogenesis pathway, e.g. PI3K, Akt, p38 and ERK1/2. Our in vivo studies demonstrated the ability of astilbin to significantly restore the blood vessel loss induced by VRI in a VRI-induced vascular insufficiency zebrafish model. In conclusion, in this study we first demonstrate that astilbin exhibits pro-angiogenic activity in HUVECs and VRI-induced vascular insufficient zebrafish, possibly through the activation of the PI3K/Akt and MAPK/ERK dependent signaling pathways. These findings suggest that astilbin could be further developed as a potential agent in the prevention or treatment of insufficient angiogenesis related diseases in the future.

A simple lateral flow biosensor for rapid detection of lead(ii) ions based on G-quadruplex structure-switching.

A novel lateral flow biosensor for rapid detection of Pb2+ was established for the first time based on Pb2+-induced G-quadruplex structure-switching. Semi-quantitative results could be read by reference to a colorimetric card. The whole process only took 15 minutes with a visual detection limit of 25 nM.

Oxygen-Free Biochemistry: The Putative CHN Foundation for Exotic Life in a Hydrocarbon World?

Since Earth's biochemistry is carbon-based and water-borne, the main strategies for searching for life elsewhere are "follow the carbon" and "follow the water." Recently, however, there is a growing focus on the prospect that putative exotic life on other planets could rely on unearthly biochemistries. Here, we hypothesize a novel oxygen-free organic chemistry for supporting potential exotic biosystems, which is named CHN biochemistry. This oxygen-free CHN biochemistry starts from simple oxygen-free species (including hydrocarbons, hydrogen cyanide, and nitriles) and produces a range of functional macromolecules that may function in similar ways to terran macromolecules, such as sugars (cyanosugars), acids (cyanoacids), amino acids (amino cyanoacids), and nucleobases (cyanonucleobases). These CHN macromolecules could further interact with each other to generate higher "cyanoester" and "cyanoprotein" systems. In addition, theoretical calculations indicate that the energy changes of some reactions are consistent with their counterparts in Earth's biochemistry. The CHN biochemistry-based life would be applicable in habitats with a low bioavailability of oxygen, such as the alkane lakes of Titan and non-aquatic liquids on extrasolar bodies. Key Words: Oxygen-free biochemistry-Titan-Hydrocarbons-Hydrogen cyanide-Nitriles. Astrobiology 17, 1173-1181.

Co-assembly of Au nanorods with Ag nanowires within polymer nanofiber matrix for enhanced SERS property by electrospinning.

Gold nanorods (AuNRs) can be successfully co-assembled with Ag nanowires (AgNWs) to form a kind of AuNR-AgNW nanocomposite by electrostatic attraction, in which the AuNRs are arranged along the long axial direction of the AgNWs with a preferential string-like alignment. The assembled AuNR-AgNW nanocomposites are then further embedded within polyvinyl alcohol (PVA) nanofibers by electrospinning, by which both AuNRs and AgNWs can be stabilized and arranged along the axis of polymer nanofibers. When the polymer nanofibers are aligned by collecting on a copper mesh with a woven structure, the AuNR-AgNW nanocomposites assembled within the electrospun nanofibers are also arranged. The influences of the AuNR-AgNW assemblies with different amounts of AuNRs attached on AgNWs on the optical properties and surface enhanced Raman scattering (SERS) enhancement have been investigated. The resulting AuNR-AgNW/PVA electrospun mats show red-shifted and broader absorption bands and higher SERS performances compared with the normal casting films with randomly dispersed AuNRs and AgNWs, or electrospun mats with monometallic components, due to the order alignment of AuNR-AgNW nanocomposites on a large scale.

Controlled assemblies of gold nanorods in PVA nanofiber matrix as flexible free-standing SERS substrates by electrospinning.

Under control: Controlled assemblies of gold nanorods in a poly(vinyl alcohol) (PVA) nanofiber matrix with tunable optical properties can be achieved by using electrospinning. The resultant assemblies can be used as substrates for surface-enhanced Raman spectroscopy (SERS). This work provides a facile way to control alignment of anisotropic nanostructures in a polymer nanofiber matrix and generates new assemblies with interesting properties.