The coupling of Phanerozoic continental weathering and marine phosphorus cycle.

Organic matter production and decomposition primarily modulate the atmospheric O2 and CO2 levels. The long term marine primary productivity is controlled by the terrestrial input of phosphorus (P), while the marine P cycle would also affect organic matter production. In the past 540 million years, the evolution of terrestrial system, e.g. colonization of continents by vascular land plants in late Paleozoic, would certainly affect terrestrial P input into the ocean, which in turn might have impacted the marine primary productivity and organic carbon burial. However, it remains unclear how the marine P cycle would respond to the change of terrestrial system. Here we reconstruct the secular variations of terrestrial P input and biological utilization of seawater P in Phanerozoic. Our study indicates that riverine dissolved P input and marine P biological utilization (i.e. the fraction of P being buried as organophosphorus) are inversely correlated, suggesting the coupling of continental P input and marine P cycle. We propose an increase of P input would elevate surface ocean productivity, which in turn enhances marine iron redox cycle. Active Fe redox cycle favors the scavenging of seawater P through FeOOH absorption and authigenic phosphate formation in sediments, and accordingly reduces the bioavailability of seawater P. The negative feedback of marine P cycle to terrestrial P input would keep a relatively constant organic carbon burial, limiting the variations of surface Earth temperature and atmospheric O2 level.

Early animal evolution and highly oxygenated seafloor niches hosted by microbial mats.

The earliest unambiguous evidence for animals is represented by various trace fossils in the latest Ediacaran Period (550-541 Ma), suggesting that the earliest animals lived on or even penetrated into the seafloor. Yet, the O2 fugacity at the sediment-water interface (SWI) for the earliest animal proliferation is poorly defined. The preferential colonization of seafloor as a first step in animal evolution is also unusual. In order to understand the environmental background, we employed a new proxy, carbonate associated ferrous iron (Fecarb), to quantify the seafloor oxygenation. Fecarb of the latest Ediacaran Shibantan limestone in South China, which yields abundant animal traces, ranges from 2.27 to 85.43 ppm, corresponding to the seafloor O2 fugacity of 162 µmol/L to 297 µmol/L. These values are significantly higher than the oxygen saturation in seawater at the contemporary atmospheric pO2 levels. The highly oxygenated seafloor might be attributed to O2 production of the microbial mats. Despite the moderate atmospheric pO2 level, microbial mats possibly provided highly oxygenated niches for the evolution of benthic metazoans. Our model suggests that the O2 barrier could be locally overcome in the mat ground, questioning the long-held belief that atmospheric oxygenation was the key control of animal evolution.

Multi-functional Liposomes Enhancing Target and Antibacterial Immunity for Antimicrobial and Anti-Biofilm Against Methicillin-Resistant Staphylococcus aureus.

PURPOSE: The aim of this study was to prepare wheat germ agglutinin (WGA)-modified liposomes encapsulating clarithromycin and to evaluate their in vitro and in vivo efficacy against Methicillin-resistant Staphylococcus aureus (MRSA). METHODS: Physicochemical parameters, minimum inhibitory concentrations, in vitro killing kinetic, cellular uptake, biofilm formation inhibition and pre-formed biofilm destruction, biodistribution, in vivo antibacterial efficacy against MRSA, and phagocytosis into macrophages for liposomes loading clarithromycin were determined. RESULTS: The minimum inhibitory concentration and the time-kill curve for WGA-modified liposomal clarithromycin were better than those of free and nonmodified liposomal clarithromycin. Flow cytometry analysis displayed that liposomes could deliver more Coumarin 6, a fluorescent probe, into bacteria because of the conjugation of WGA. Besides, WGA-modified liposomal clarithromycin inhibited formation of S. aureus (ATCC 29213) and MRSA biofiom, and prompted the biofilm disassembly at lower concentrations below MIC. Effective accumulation of liposomes was displayed in the enterocoelia of the mice because of WGA. The number of MRSA colony-forming units in the kidney and spleen in mice treated with WGA-modified liposomal clarithromycin was significantly lower than that treated with free and nonmodified clarithromycin (p < 0.05). Intracellular localization of MRSA occurred in a significantly higher proportion of macrophage exposed to WGA-modified liposomes compared to those exposed to nonmodified liposomes. CONCLUSIONS: Liposome modified by WGA is a promising formulation for bacteria targeted delivery and immunity defensive system through macrophage improving uptake of bacteria, biodistribution, in vitro and in vivo antibacterial efficacy against MRSA.

Bleomycin A6-loaded anionic liposomes with in situ gel as a new antitumoral drug delivery system.

The goal is to develop an in situ gel system comprising anionic liposomes (AL) containing bleomycin A6 (BLM A6) dispersed within the thermosensitive in situ gel for sustained release. The results indicated that the gelation temperature decreased due to AL within gel. Similarly, viscosity and mechanical parameters, such as gel strength for gel, could be enhanced by inducing lipid material with negative charge (phosphatidylglycerol) at 37 °C, which provided against corrosion at physiological condition. The in vitro release experiments performed with a dialysis method revealed that in situ gel with AL exhibited the longer drug-release period compared to that with or without nonionic liposomes. An in vivo fluorescence imaging study suggested that the gel with AL loading FITC-BLM A6 stayed in administration site at least for five days. A thermosensitive in situ gel with anionic liposome was a promising carrier for hydrophilic BLM A6, to be used in parenteral delivery system for anti-tumor treatment.

Co-delivery of honokiol, a constituent of Magnolia species, in a self-microemulsifying drug delivery system for improved oral transport of lipophilic sirolimus.

Sirolimus is recognized as a P-glycoprotein (P-gp) substrate with poor water-solubility. To improve its solubility and bioabsorption, self-microemulsifying drug delivery systems (SMEDDS) containing a novel P-gp inhibitor, honokiol, were prepared. The aim of this work was to evaluate the enhanced transport of sirolimus SMEDDS as well as the roles of honokiol. In situ single-pass intestinal perfusion and in vitro human colon adenocarcinoma (Caco-2) cell models were applied to study the effects of honokiol within SMEDDS on the transport of sirolimus. The results indicated that a combination of honokiol with sirolimus in SMEDDS did not significantly alter the particle size, polydispersity index and release of drugs. In addition, the absorption rate constant (Ka) as well as the effective permeability coefficients (Peff) of sirolimus in situ intestinal absorption, and the apparent permeability coefficients (Papp) of sirolimus in caco-2 cells were significantly enhanced by cremophor EL-based SMEDDS with honokiol as compared with those of SMEDDS without honokiol. Rhodamine123 uptake rate in caco-2 cells and in vitro cytotoxicity of sirolimus were enhanced by honokiol in SMEDDS indicating a substantial P-gp inhibition of honokiol. In conclusion, coadministration of honokiol with poor soluble P-gp substrate in SMEDDS, could serve as a favorable approach for oral delivery.

Sirolimus-loaded polymeric micelles with honokiol for oral delivery.

OBJECTIVES: The aims of the present study were to design polymeric micelles loading sirolimus with honokiol to increase drug solubility and to gain an insight into the effect of honokiol on oral transport of P-glycoprotein substrate (P-gp). METHODS: Particle size distribution, encapsulation efficiency, drug-loading content and in-vitro release of sirolimus-loaded micelles with honokiol were determined. Transport of sirolimus-loaded micelles across Caco-2 cell monolayers and jejunum segment of rats were investigated. In-vitro cytotoxicity experiments and the cellular uptake study were carried out via sulforhodamine B assay and flow cytometry, respectively. KEY FINDINGS: A coadministration of honokiol with sirolimus in micelles did not significantly modify the particle size, polydispersity index and release of drugs demonstrating successful loading within the micelles. The apparent transport coefficients (Papp ) and effective permeability (Peff ) of sirolimus were increased with more amount of honokiol loaded in micelles. Cellular uptake study demonstrated that rhodamine123 uptake rate was enhanced by honokiol-loaded micelles, indicating substantial P-gp inhibition action by honokiol and mPEG-PLA-based micelles. CONCLUSION: Oral transport of sirolimus was significantly improved by coadministration with honokiol, an inhibitor of the P-gp, in polymeric micelles formulation.

Effect of peritumoral injection of boanmycin hydrochloride within temperature-sensitive in situ gel using Hep-G2 hepatoma nude mice model.

BACKGROUND: Boanmycin hydrochloride, a new antitumor agent, has a short half-life and fast clearance speed in vivo. The aim of this research was to investigate the effectiveness of peritumor injection of boanmycin hydrochloride within temperature-sensitive gel in situ using Hep-G2 hepatoma nude mice model. METHODS: Nude mice with human Hep-G2 tumor in right flank were randomly divided into four groups: normal saline group, in situ gel only group, boanmycin hydrochloride in situ saline group, and boanmycin hydrochloride in situ gel group, and were treated with injection of corresponding agents into peripheral tissue of the tumor. The volume of the tumor and the body weight of the mice were regularly measured, and tumor growth curve was generated. The size, internal echo, and blood flow of the tumors were observed by color Doppler ultrasonography. Histopathologic changes of the tumor after treatment were observed under both optical and transmission electron microscopy. RESULTS: The tumor growth was significantly inhibited by peritumoral therapy in boanmycin hydrochloride in situ gel group with the tumor inhibitory rate of 86.76%. The blood flow of the tumor was still seen in both normal saline group and in situ gel only group on color Doppler ultrasound. Punctate calcification and dotted blood flow were seen in boanmycin hydrochloride group; however, there was massive calcification and no blood flow in the tumor in the boanmycin hydrochloride in situ gel group. Large areas of necrosis and apoptotic cells were shown by microscopic observation in boanmycin hydrochloride in situ gel group. CONCLUSION: Temperature-sensitive boanmycin hydrochloride in situ gel can effectively delay the release of boanmycin hydrochloride and increase its anticancer effects for liver cancer in animal model.

[In vivo distribution of FITC-labeled boanmycin hydrochloride in situ gel].

This study is to evaluate the sustained-release effect of the thermosensitive in situ gel for injection of boanmycin hydrochloride (BAM) by bioluminescence imaging in nude mice. BAM was labeled with fluorescein isothiocyanate (FITC). The FITC-labeled BAM (FITC-BAM) was purified by dialysis and Sephadex G25 gel column, and then was identified by matrix-assisted laser desorption ionization/time of flight (MALDI-TOF). The model of experimental hepatoma HepG-2 nude mice was established, and the optical imaging system was applied to evaluate the distribution of FITC-BAM in vivo. Results of MALDI-TOF proved that the major molecular ratio of BAM : FITC was 1 : 1 or 1 : 2. Bioluminescence imaging showed that the diffusion of FITC-BAM in situ gel group was significantly delayed compared with the negative control group. This study demonstrated that the thermosensitive in situ gel can effectively delay the release of boanmycin hydrochloride, and extend the retention time in vivo.

[Thermosensitive in situ gel of boanmycin hydrochloride for injection].

Poloxamer F127, poloxamer F68 and hydroxypropyl methylcellulose K4M were used to prepare the thermosensitive in situ gel of boanmycin hydrochloride for injection. Its gelation temperature, rheological behavior, texture characteristics, scanning electron microscopy, in vitro and in vivo drug release were evaluated. These results showed that the formulation was a fluid solution at room temperature, which could become semisolid at the temperature of 37 degrees C, and the thermally induced sol-gel transition allowed to be injectable and in situ setting. The formulation was constructed into a tridimensional network at gelation temperature. The drug release was controlled by the diffusion of the drug and the erosion of the gelmatrix. The pharmacokinetics indicated that the drug could be released slowly for up to 48 hours after subcutaneous administration in rats.