Piezocatalytically-induced controllable mineralization scaffold with bone-like microenvironment to achieve endogenous bone regeneration.

Orderly hierarchical structure with balanced mechanical, chemical, and electrical properties is the basis of the natural bone microenvironment. Inspired by nature, we developed a piezocatalytically-induced controlled mineralization strategy using piezoelectric polymer poly-L-lactic acid (PLLA) fibers with ordered micro-nano structures to prepare biomimetic tissue engineering scaffolds with a bone-like microenvironment (pcm-PLLA), in which PLLA-mediated piezoelectric catalysis promoted the in-situ polymerization of dopamine and subsequently regulated the controllable growth of hydroxyapatite crystals on the fiber surface. PLLA fibers, as analogs of mineralized collagen fibers, were arranged in an oriented manner, and ultimately formed a bone-like interconnected pore structure; in addition, they also provided bone-like piezoelectric properties. The uniformly sized HA nanocrystals formed by controlled mineralization provided a bone-like mechanical strength and chemical environment. The pcm-PLLA scaffold could rapidly recruit endogenous stem cells, and promote their osteogenic differentiation by activating cell membrane calcium channels and PI3K signaling pathways through ultrasound-responsive piezoelectric signals. In addition, the scaffold also provided a suitable microenvironment to promote macrophage M2 polarization and angiogenesis, thereby enhancing bone regeneration in skull defects of rats. The proposed piezocatalytically-induced controllable mineralization strategy provides a new idea for the development of tissue engineering scaffolds that can be implemented for multimodal physical stimulation therapy.

Involvement of P-gp on Reversing Multidrug Resistance Effects of 23-Hydroxybetulinic Acid on Chemotherapeutic Agents.

Betulinic acid (BA) and 23-Hydroxybetulinic acid (23-HBA) are natural products with similar structures, which show a range of biological effects including cytotoxicity activity. The aim of current research was to investigate and evaluate the combinational cytotoxicity of BA and 23-HBA with chemotherapeutic agents in vitro, and to clarify the potential interaction and related mechanism with P-gp. Instead of BA, 23-HBA could increase cytotoxicity of MCF-7/ADR cells to adriamaycin (ADR) and vincristine (VCR). The intracellular accumulation of ADR/VCR in MCF-7/ADR cells was obviously increased in the presence of 23-HBA. Furthermore, 23-HBA could show dose-dependent increase on the transport of VCR and digoxin, which are typical P-gp substrates, in both MDCK-MDR1 and Caco-2 cells. However, the transport of BA and 23-HBA was not influenced by P-gp inhibition in MDCK-MDR1 cells. MDR1 shift assay and molecular docking model suggested that both compounds showed interaction with P-gp, yet the binding affinity and sites are different. In conclusion, 23-HBA could strongly improve the efficacy of anti-tumor agents in multidrug resistance (MDR) cells, which was related to P-gp inhibition. The MDR1 shift assay and molecular docking study further revealed that 23-HBA and BA showed different interaction modes with P-gp.

Identification of possible reductants in the aqueous leaf extract of mangrove plant Rhizophora apiculata for the fabrication and cytotoxicity of silver nanoparticles against human osteosarcoma MG-63 cells.

Rhizophora apiculata is a less studied tannin-rich plant of the mangrove ecosystem with potent biomedical applications. Tannins have been known to reduce silver ions into silver nanoparticles which in particular are known to possess cytotoxic effects against a variety of cancer cells. The aqueous leaf extract was prepared and quantitatively analyzed for its phytochemical content. According to the quantitative phytochemical analysis, the extract was rich in tannins and other reducing sugars. The reducing sugar-rich extract was further used for the synthesis of silver nanoparticles. Taking these facts into consideration, in this study, an eco-friendly approach was followed to biosynthesize silver nanoparticles using a tannin-rich Rhizophora apiculata aqueous leaf extract. The synthesized nanoparticles were partially characterized by our previous reports. This report further characterizes the particles by determining its average size, polydispersity index and zeta potential using dynamic light scattering. After characterization, the nanoparticles were tested for cytotoxic effects against human osteosarcoma MG-63 cells. The effects were analyzed by microscopic observation and MTT assay. The results indicate that the tannin-rich extract reduced the precursor silver nitrate into silver nanoparticles of favorable size for tumor infiltration. The nanoparticles possessed significant cytotoxic effects against MG-63 cells which could be possibly attributed to the antioxidant activity of silver nanoparticles. Further studies at the molecular level can indicate its potential in nanomedicine for the treatment of bone cancer at the clinical level.

Berberine induces GLP-1 secretion through activation of bitter taste receptor pathways.

Our previous studies revealed that berberine-mediated GLP-1 secretion was a possible mechanism for berberine exerting good effects on hyperglycemia. This study was designed to ascertain whether berberine-induced secretion of GLP-1 was related with activation of bitter taste receptors expressed in gastrointestinal tract. Western blotting results showed that TAS2R38, a subtype of bitter taste receptor, was expressed on human enteroendocrine NCI-H716 cells. GLP-1 secretion induced by berberine from NCI-H716 cells was inhibited by incubation with anti-TAS2R38 antibody. We further performed gene silencing using siRNA to knockdown TAS2R38 from NCI-H716 cells, which showed that siRNA knockdown of the TAS2R38 reduced berberine-mediated GLP-1 secretion. We adopted inhibitors of PLC and TRPM5 known to be involved in bitter taste transduction to investigate the underlying pathways mediated in berberine-induced GLP-1 secretion. It was found that PLC inhibitor U73122 inhibited berberine-induced GLP-1 release in NCI-H716 cells, while TRPM5 blocker quinine failed to attenuate berberine-induced secretion of GLP-1. The present results demonstrated that berberine stimulated GLP-1 secretion via activation of gut-expressed bitter taste receptors in a PLC-dependent manner. Because berberine was found to be a ligand of bitter taste receptor, the results of present study may provide an explanation for some bitter taste substance obtain hypoglycemic effect.

Pharmacokinetic synergy from the taxane extract of Taxus chinensis improves the bioavailability of paclitaxel.

BACKGROUND: Taxus chinensis (Pilger) Rehd is widely distributed in China and the northern hemisphere, and the most popular medicinal component isolated from Taxus chinensis is paclitaxel (PTX), which has now become the first-line chemotherapeutic drug for breast cancer and ovarian cancer. Oral administration of pure PTX as a potential anti-cancer agent is compromised by low bioavailability. HYPOTHESIS/PURPOSE: In the clinical practice of traditional Chinese medicine, drug co-administration in the form of mixtures or formula could achieve pharmacokinetic/pharmacodynamic synergies. In this study, we aimed to investigate whether there exist any 'inherent' phytochemical synergy from Taxus chinensis extract that could improve PTX bioavailability. STUDY DESIGN: Pharmacokinetic study of PTX after oral administration of Taxus chinensis extracts or single PTX was performed. In addition, comparative cytotoxic studies were carried out on the MCF-7 breast cancer cell lines. METHODS: The plasma concentrations of PTX were determined using a validated high performance chromatography tandem mass spectrometry method. The cytotoxicity was compared using the MTT assay. RESULTS: Oral administration of taxane fractions isolated from Taxus chinensis (containing 17.2% PTX) could achieve remarkably higher blood concentration and systemic exposure of PTX in rats, while the retention of PTX was significantly improved. Further tissue distribution analysis revealed that the penetration of PTX into major tissues was drastically increased compared with that of single PTX. In addition, in MCF-7 cells, the co-existing components in taxane mixtures could strengthen the inhibitory effects of PTX on tumor cell proliferation. CONCLUSION: Together, these results support that administration of PTX in the form of taxane mixtures may become a novel approach to improve the poor bioavailability of PTX. Moreover, the inherent synergy from Taxus chinensis taxane extracts promises a novel strategy to strengthen PTX efficacy.

23-Hydroxybetulinic acid from Pulsatilla chinensis (Bunge) Regel synergizes the antitumor activities of doxorubicin in vitro and in vivo.

UNLABELLED: ETHNOPHARMACOLOGICAL REVELANCE: Pulsatilla chinensis (Bunge)Regel has been used as adjuvant in chemotherapy in traditional Chinese medicine. 23-Hydroxybetulinic acid, an isolated pentacyclic triterpene, is the major active constituent of Pulsatilla chinensis (Bunge) Regel. AIM OF THIS STUDY: To evaluate the combinational anticancer effect of 23-hydroxybetulinic acid and doxorubicin in vitro and in vivo. MATERIALS AND METHODS: The effect of combination treatment with 23-hydroxybetulinic acid and doxorubicin was evaluated with a quantitative combination index method based on the median-effect analysis in various cancer cell lines. And in vivo efficacy of combination chemotherapy was also evaluated using ICR mice bearing sarcoma 180 carcinoma tumors. RESULTS: 23-Hydroxybetulinic acid showed a synergistic cytotoxic effect on multiple cancer cell lines by combined use with doxorubicin. In vivo studies further demonstrated that co-administration of 23-HBA significantly improved the sensitivity of the tumor to doxorubicin through increasing intra-tumor doxorubicin concentration and inhibiting doxorubicin-induced up-regulation of P-gp in tumor. CONCLUSION: These results suggest that the combined therapy with 23-hydroxybetulinic acid and doxorubicin may be a new promising strategy to promote the clinical chemotherapy, which needs further verification.