A multi-hit therapeutic nanoplatform for hepatocellular carcinoma: Dual stimuli-responsive drug release, dual-modal imaging, and in situ oxygen supply to enhance synergistic therapy.

Nanomedicine has been widely studied for the diagnosis and treatment of hepatocellular carcinoma (HCC). How to synthesize a nanoplatform possessing a high synergistic therapeutic efficacy remains a challenge in this emerging research field. In this study, a convenient all-in-one therapeutic nanoplatform (FTY720@AM/T7-TL) is designed for HCC. This advanced nanoplatform consists of multiple functional elements, including gold-manganese dioxide nanoparticles (AM), tetraphenylethylene (T), fingolimod (FTY720), hybrid-liposome (L), and T7 peptides (T7). The nanoplatform is negatively charged at physiological pH and can transit to a positively charged state once moving to acidic pH environments. The specially designed pH-responsive charge-reversal nanocarrier prolongs the half-life of nanodrugs in blood and improves cellular uptake efficiency. The platform achieves a sustained and controllable drug release through dual stimulus-response, with pH as the endogenous stimulus and near-infrared as the exogenous stimulus. Furthermore, the nanoplatform realizes in situ O2 generation by catalyzing tumor over-expressed H2O2, which alleviates tumor microenvironment hypoxia and improves photodynamic therapy. Both in vitro and in vivo studies show the prepared nanoplatform has good photothermal conversion, cellular uptake efficiency, fluorescence/magnetic resonance imaging capabilities, and synergistic anti-tumor effects. These results suggest that the prepared all-in-one nanoplatform has great potential for dual-modal imaging-guided synergistic therapy of HCC.

An injectable thermosensitive hydrogel loaded with a theranostic nanoprobe for synergistic chemo-photothermal therapy for multidrug-resistant hepatocellular carcinoma.

Multi-drug resistance (MDR) is a complicated cellular defense mechanism for tumor cells to resist chemotherapy drugs, which is also the main cause of chemotherapy failure. In this study, a local injectable hydrogel delivery system was used to construct an on-demand sustained-release platform with the advantages of chemotherapy, photothermal therapy (PTT), and magnetic resonance imaging (MRI). It could achieve synergistic chemo-photothermal therapy and real-time evaluation of the therapeutic effects (via MRI) for MDR hepatocellular carcinoma (HCC). Furthermore, after a single administration, the prepared hydrogel with a theranostic nanoprobe could release the therapeutic agents on demand for up to 14 d. Firstly, doxorubicin (DOX) and gold-manganese oxide (Au-MnO) nanoparticles (NPs) were incorporated into liposome-based self-assembled micelles, then loaded into the thermosensitive hydrogel (F127) to form DOX@Au-MnO-L NPs/F127 hydrogel (DAML/H). The prepared NP complex showed a spherical morphology with a narrow size distribution. The prepared hydrogel drug delivery system had injectable properties and stable photothermal conversion. Both the DOX@Au-MnO-L NPs and DAML/H showed controlled drug release under near infrared (NIR) laser irradiation. The in vitro MRI studies indicated that the prepared DAML/H had a high relaxation rate (14.38 mM-1 s-1) and good MRI scanning sensitivity conditions. The in vitro and in vivo results suggested the synergistic chemo-photothermal therapy of DAML/H with NIR irradiation (808 nm, 1 W cm-2, 10 min) improved the antitumor efficacy for MDR HCC. The in vivo retention experiment of Au in tumors indicated that the prepared hydrogel drug delivery system (DAML/H) had a good ability to retain Au in the tumor for a long time (at least 14 d). The western blotting results revealed that DAML/H with laser treatment could effectively downregulate P-glycoprotein (P-gp), p53 and antiapoptotic protein (Bcl-2), whereas the expression level of proapoptotic protein (Bax) and caspase-3 were increased. Therefore, DAML/H could serve as a promising synergistic chemo-photothermal therapy for MDR HCC, and a single administration might achieve long-term (14 d), on-demand, sustained-release treatment of tumors.

Uncommon Behavior of Li Doping Suppresses Oxygen Redox in P2-Type Manganese-Rich Sodium Cathodes.

Utilizing both cationic and anionic oxygen redox reactions is regarded as an important approach to exploit high-capacity layered cathode materials with earth abundant elements. It has been popular strategies to effectively elevate the oxygen redox activities by Li-doping to introduce unhybridized O 2p orbitals in Nax MnO2 -based chemistries or enabling high covalency transition metals in P2-Na0.66 Mnx TM1- x O2 (TM = Fe, Cu, Ni) materials. Here, the effect of Li doping on regulating the oxygen redox activities P2-structured Na0.66 Ni0.25 Mn0.75 O2 materials is investigated. Systematic X-ray characterizations and ab initio simulations have shown that the doped Li has uncommon behavior in modulating the density of states of the neighboring Ni, Mn, and O, leading to the suppression of the existing oxygen and Mn redox reactivities and the promotion of the Ni redox. The findings provide a complementary scenario to current oxygen redox mechanisms and shed lights on developing new routes for high-performance cathodes.

Comparative toxicity of five dispersants to test organisms at different trophic levels: Platymonas helgolandica, Ruditapes philippinarum, and Acinetobacter sp. Tox2.

Nowadays, although dispersants have been widely applied for emergency response to oil spills, they are potentially hazardous to the marine ecosystem. Therefore, it is necessary to evaluate dispersants' toxicity in a practical and integrated way before their large-scale application. Here, we compared the acute toxicity of five chemical dispersants (concentrate RS-I, conventional RS-I, HLD-501, Fuken-2, and Weipu) to three species (a microalgae Platymonas helgolandica, a mollusk Ruditapes philippinarum, and a luminescent bacterium Acinetobacter sp. Tox2) which represent different trophic levels. Our results showed that (1) conventional RS-I was slightly toxic to all the three test organisms; (2) concentrate RS-I and Weipu were slightly toxic to R. philippinarum, but were not toxic to the other two test species; (3) Fuken-2 and HLD-501 exhibited no acute toxicity to the three test organisms. Our results could provide information on toxicity data derived from multiple test organisms for the use of these five dispersants in the future.

Determination of 11 Phthalate Esters in Beverages by Magnetic Solid-Phase Extraction Combined with High-Performance Liquid Chromatography.

Background: Beverages can be easily contaminated by phthalate esters (PAEs) during the production, bottling, and transportation processes. It is necessary to determine the contamination level in beverages for assessment of human exposure. Objective: In this study, magnetic solid-phase extraction (MSPE) was combined with HPLC for the determination of 11 PAEs in beverages. Methods: Self-synthesized magnetic multiwalled carbon nanotubes (m-MWCNTs) were used as the adsorbent for PAE extraction. To extract the PAEs, an appropriate amount of m-MWCNTs and NaCl was added to the beverage sample. The mixture was mixed on a vortex mixer, the magnetic sorbent was collected with the aid of a magnet, and the supernatant was removed. Then, the analytes were eluted with n-hexane-acetone (1+1, v/v). Finally, the eluent was analyzed by the HPLC method. The separation was accomplished on a Phenomenex Luna-C18 column (250 × 4.6 mm, 5 µm), and the detection wavelength was set at 225 nm. Results: The linear ranges of the method were 2-300 µg/L with correlation coefficients greater than 0.9981. The LOD and LOQ were in the range of 0.659-5.33 × 10-2 µg/L and 2.20-17.8 × 10-2 µg/L, respectively. The recoveries of the method ranged from 79.8 to 114%, with the relative SDs less than 15.8%. The established method has been successfully applied for the determination of 11 PAEs in mineral water, carbonated soft drink, tea beverage, and fruit juice samples. PAEs were detected at 0.246-34.3 µg/L in these samples. Conclusions: The m-MWCNTs are the satisfactory sorbent for MSPE because of their strong adsorption capacity for PAEs. The established MSPE-HPLC method is rapid, easy, sensitive, green, and cost-effective. It can be applied to the analysis of trace PAEs in plastic bottled beverages. Highlights: Three magnetic nanoparticles (MNPs), including Fe3O4 MNPs, m-MWCNTs, and magnetic graphene oxide, were synthesized, and m-MWCNTs were chosen as the sorbent of MSPE for PAE extraction because of their strong adsorption capacity for PAEs. An MSPE-HPLC method has been developed for the analysis of 11 phthalates in plastic bottled beverages. The established method was successfully applied to the analysis of 11 phthalates in four types of beverage samples.

Validation of a rapid and simple high-performance liquid chromatography-electrospray ionization-mass spectrometry method for simultaneous analysis of 15 key chemicals in slimming foods and herbal products.

A rapid and simple high-performance liquid chromatography/electrospray ionization tandem mass spectrometry method was developed for simultaneous analysis of 15 key chemicals in slimming foods and herbal products. These chemicals were strictly restricted adulterants (phenolphthalein, sibutramine, fenfluramine, clopamide, ephedrine, norpseudoephedrine, caffeine and phenformin) and physiologically relevant active components (l-carnitine, nuciferine, aloe-emodin, rhein, emodin, chrysophanol and physcion). In multi-day validations, intra- (n = 5) and inter-day precision (n = 3), limits of detection and limits of quantification for all analytes were 0.60-7.22%, 0.75-9.45%, 0.09-10 µg/L and 0.30-33.3 µg/L, respectively. Mean recovery ranged from 71.4% to 116% for all analytes in three representative samples. The method was validated on 17 samples including 12 kinds of slimming foods and five kinds of herbal products, and was shown to be ideal for routine quantification of 15 key chemicals in slimming foods and herbal products, providing an efficient strategy for quality control and food safety evaluation of weight reducing supplements.

Study on immobilization of marine oil-degrading bacteria by carrier of algae materials.

This study investigated the immobilizations with of bacteria two kinds of algal materials, Enteromorpha residue and kelp residue. The lipophilicity of them were compared by diesel absorption rates. The immobilization efficiency of Bacillus sp. E3 was measured to evaluate whether these carriers would satisfy the requirement for biodegradation of oil spills. The bacteria were immobilized through adsorption with the sterilized and non-sterilized carriers to compare the differences between the two treatments. Oil degradation rates were determined using gravimetric and GC-MS methods. Results showed the absorption rates of Enteromorpha residue and kelp residue for diesel were 411 and 273% respectively and remained approximately 105 and 120% after 2 h of erosion in simulated seawater system. After immobilized of Bacillus sp. E3, the oil degradation rates of them were higher than 65% after 21 days biodegradations. GC-MS analysis showed that two immobilizations degraded higher than 70% of the total alkane and the total PAHs, whereas the free bacteria degraded 63% of the total alkane and 66% the total PAHs. And the bacteria immobilized with the carriers degraded more HMW-alkanes and HMW-PAHs than the free bacteria. The bacteria immobilized by non-sterilized kelp residue showed a considerably higher degradation rate than that using sterilized kelp residue. A considerably higher cells absorption rate of immobilization was obtained when using kelp residue, and the preparation of immobilization was low cost and highly efficient. The experiments show the two algae materials, especially the kelp residue, present potential application in bioremediation of marine oil spills.

A convenient ultrasound-assisted saponification for the simultaneous determination of vitamin E isomers in vegetable oil by HPLC with fluorescence detection.

An efficient ultrasound-assisted saponification was developed for simultaneous determination of vitamin E isomers in vegetable oil by high-performance liquid chromatography with fluorescence detection. The samples were saponified ultrasonically with potassium hydroxide solution for only 7 min, then the analytes were extracted with ether. Vitamin E isomers were separated on a C18 column at 25°C with a mobile phase of methanol/acetonitrile (81:19, v/v) at a flow rate of 0.8 mL/min. Fluorescence detection was operated at 290 nm of excitation wavelength and 327 nm of emission wavelength. Under the optimized conditions, good linearities over the range of 0.001-8.00 µg/mL (r > 0.999) were obtained. Mean recoveries of the method were 88.0-106%, with intra- and interday RSDs less than 11.8 and 12.8%, respectively. The detection limits and quantification limits of the method were 0.30-1.8 and 1.0-6.1 µg/kg, respectively. The recoveries of this method were much higher than that of the quick, easy, cheap, effective, rugged, and safe method and direct dilution method, but were similar to those of hot saponification. This proposed method provides reliable, simple, and rapid quantification of vitamin E isomers in vegetable oils. Five kinds of vegetable oils were analyzed, the quantification results were within the ranges reported by other authors.

Recovered insulin production after thiamine administration in permanent neonatal diabetes mellitus with a novel solute carrier family 19 member 2 (SLC19A2) mutation.

BACKGROUND: Solute carrier family 19 member 2 (SLC19A2) gene deficiency is one of the causes of permanent neonatal diabetes mellitus (PNDM) and can be effectively managed by thiamine supplementation. Herein we report on a male patient with a novel SLC19A2 mutation and summarize the clinical characteristics of patients with SLC19A2 deficiency. METHODS: The genetic diagnosis of the patient with PNDM was made by sequencing and quantitative polymerase chain reaction. The clinical characteristics of PNDM were summarized on the basis of a systematic review of the literature. RESULTS: The patient with PNDM had c.848G>A (p.W283X) homozygous mutation in SLC19A2. His father had a wild-type SLC19A2 (c.848G) and his mother was c.848G/A heterozygous. The patient and his father both had a diploid genotype (c.848A/A and c.848G/G). After oral thiamine administration, the patient's fasting C-peptide levels increased gradually, and there was a marked decrease in insulin requirements. A search of the literature revealed that thiamine treatment was effective and improved diabetes in 63% of patients with SLC19A2 deficiency. CONCLUSIONS: A novel SLC19A2 mutation (c.848G>A; p.W283X) was identified, which was most likely inherited as segmental uniparental isodisomy. Insulin insufficiency in PNDM caused by SLC19A2 deficiency can be corrected by thiamine supplementation. The differential diagnosis of SLC19A2 deficiency should be considered in children with PNDM accompanied by anemia or hearing defects to allow for early treatment.

Redox Transformations of As and Se at the Surfaces of Natural and Synthetic Ferric Nontronites: Role of Structural and Adsorbed Fe(II).

Adsorption and redox transformations on clay mineral surfaces are prevalent in surface environments. We examined the redox reactivity of iron Fe(II)/Fe(III) associated with natural and synthetic ferric nontronites. Specifically, we assessed how Fe(II) residing in the octahedral sheets, or Fe(II) adsorbed at the edge sites alters redox activity of nontronites. To probe the redox activity we used arsenic (As) and selenium (Se). Activation of both synthetic and natural ferric nontronites was observed following the introduction of Fe(II) into predominantly-Fe(III) octahedral sheets or through the adsorption of Fe(II) onto the mineral surface. The oxidation of As(III) to As(V) was observed via catalytic (oxic conditions) and, to a lesser degree, via direct (anoxic conditions) pathways. We provide experimental evidence for electron transfer from As(III) to Fe(III) at the natural and synthetic nontronite surfaces, and illustrate that only a fraction of structural Fe(III) is accessible for redox transformations. We show that As adsorbed onto natural and synthetic nontronites forms identical adsorption complexes, namely inner-sphere binuclear bidentate. We show that the formation of an inner-sphere adsorption complex may be a necessary step for the redox transformation via catalytic or direct oxidation pathways.

Biodiversity and degradation potential of oil-degrading bacteria isolated from deep-sea sediments of South Mid-Atlantic Ridge.

The indigenous oil-degrading bacterial consortia MARA and MARB were enriched from the deep-sea sediments of South Mid-Atlantic Ridge (MAR) with crude oil as sole carbon and energy sources. Biodiversity and community analyses showed that members of α-Proteobacteria were the key players in consortium MARA, whereas those of γ-Proteobacteria were the key players in consortium MARB, which were studied by MiSeq sequencing method. Gravimetric method estimated the oil degradation rates of MARA and MARB to be 63.4% and 85.8%, respectively, after 20d. Eleven cultivable oil degraders with different morphologies were isolated. These strains were identified as Alcanivorax, Bacillus, Dietzia, Erythrobacter, Marinobacter, Nitratireductor, and Oceanicola based on 16S rRNA gene sequences. Three strains belonging to Dietzia exhibited the highest oil degradation capability. Results indicated that the intrinsic biodegradation capacity of oil contaminants by indigenous microbial communities exists in South MAR sediments.

Simultaneous Determination of 10 Adulterants in Antihypertensive Functional Foods Using Multi-Walled Carbon Nanotubes-Dispersive Solid-Phase Extraction Coupled with High Performance Liquid Chromatography.

Consumption of functional foods based on extracts from selected herbs to alleviate hypertension is an increasingly common practice in China. Adulteration of these foods with pharmaceuticals can significantly impact a consumer's health. To control the quality of the functional foods effectively, a method for the simultaneous determination of 10 common adulterants including chlortalidone, hydrochlorothiazide, indapamide, metoprolol, nifedipine, nimodipine, nitrendipine, reserpine, triamterene and valsartan in antihypertensive functional foods was developed. The target chemicals in samples were ultrasonically extracted with acetonitrile, and then cleaned-up with multi-walled carbon natotubes-dispersive solid-phase extraction. Finally, the analytes were separated with a C18 column using binary mobile phases consisting of acetonitrile and 0.03 mol/L KH2PO4 solutions (pH 3.0). The flow rate of the mobile phase was 0.80 mL/min, and the column temperature was 35°C. The detection wavelength was set at 220 nm. The limits of detection and quantification of the method ranged from 0.014 to 0.053 and 0.047 to 0.178 µg/mL, respectively. The recoveries of the method were in the range of 80.1-98.1% with relative standard deviations <9.53%. The method was successfully applied to the determination of the target chemicals in real samples and simulated samples, and respirine was detected in one tonic wine sample with a concentration of 56.8 ± 1.2 mg/L.

Thyroid volume, goiter prevalence, and selenium levels in an iodine-sufficient area: a cross-sectional study.

BACKGROUND: Selenium (Se) is a necessary element for the biosynthesis of thyroid hormones. We investigated the relationship between selenium status, thyroid volume, and goiter in a cross-sectional study in an iodine-sufficient area. METHODS: We selected residents of Chengdu (over 18 years old and living in the city for more than 5 years) using a stratified cluster sampling technique. Fifteen hundred subjects were selected for the study, which involved a questionnaire survey, physical examination, thyroid ultrasound, serum thyroid function test, and determination of serum selenium level. Thyroid volume was calculated from the thickness, width, length, and a corrective factor for each lobe. Ultimately, 1,205 subjects completed the investigation and were included in our study. Additionally, 80 school-age children were selected to provide urine samples for urinary iodine analysis. We analyzed the data using appropriate nonparametric and parametric statistical tests. RESULTS: The median urinary iodine value was 184 µg/L in school-age children, indicating iodine sufficiency. The median serum selenium level of the 1,205 subjects was 52.63 (interquartile range [IQR] : 40.40-67.00) µg/L. The median thyroid volume was 9.93 (IQR: 7.71-12.57) mL; both log-transformed serum selenium and log-transformed thyroid volume were Gaussian distributions (P = .638 and P = .046, respectively). The prevalences of goiter and thyroid nodules were 8.8% and 18.6%. The prevalences of positive thyroid autoantibodies, thyroperoxidase autoantibodies and thyroglobulin autoantibodies were 16.7%, 12.0%, and 11.1%, respectively. In the general linear regression model, there were positive associations between serum selenium and age, and body mass index. We found no association between serum selenium and thyroid-stimulating hormone. In simple linear regression analyses, we found no association between thyroid volume and serum selenium. There were no significant differences in serum selenium between persons with or without goiter. Serum selenium was not a risk factor for goiter. CONCLUSION: In our study population, serum selenium was neither associated with thyroid volume nor with goiter in an iodine-sufficient area. More studies should be conducted by following non-goitrous persons over time and monitoring their selenium status.

Identification and quantification of free, conjugate and total phenolic compounds in leaves of 20 sweetpotato cultivars by HPLC-DAD and HPLC-ESI-MS/MS.

The study systematically investigated free, conjugate and total phenolics (phenolic acids and flavonoids) in leaves of 19 Chinese and one American sweetpotato cultivars grown in China. Three extraction/hydrolytic methods (direct extraction and acidic and basic hydrolysis) for sample preparation were employed to obtain different forms of phenolics. Twenty-nine phenolics were separated and identified using HPLC-DAD and HPLC-ESI-MS/MS. Three quercetin glycosides were characterised for the first time from this plant. Contents of the principal phenolics identified were determined by the HPLC-DAD procedure, which was validated in terms of linearity, precision, accuracy and limit of detection and quantification. Moreover, to the best of our knowledge, it is the first to reveal and demonstrate artifacts of esterification during acidic methanolic and ethanolic hydrolysis, and chromatographic behaviours, UV spectra and MS data of 20 hydroxycinnamic acid methyl and ethyl esters were obtained using acidic methanolic and ethanolic hydrolysis.

Cement proteins of the tube-building polychaete Phragmatopoma californica.

The mineralized tube of the sandcastle worm Phragmatopoma californica is made from exogenous mineral particles (sand, shell, etc.) glued together with a cement secreted from the "building organ" on the thorax of the worm. The glue is a cross-linked mixture of three highly polar proteins. The complete sequences of Pc-1 (18 kDa) and Pc-2 (21 kDa) were deduced from cDNAs derived from previously reported peptide sequences (Waite, J. H., Jensen, R., and Morse, D. E. (1992) Biochemistry 31, 5733-5738). Both proteins are basic (pI approximately 10) and exhibit Gly-rich peptide repeats. The consensus repeats in Pc-1 and -2 are VGGYGYGGKK (15 times), and HPAVXHKALGGYG (eight times), respectively, in which X denotes an intervening nonrepeated sequence and Y is modified to 3,4-dihydroxyphenyl-l-alanine (Dopa). The third protein, Pc-3, was deduced from the cement to be about 80 mol % phosphoserine/serine, and the cDNA was obtained by exploiting the presence of poly-serine repeats. Pc-3 consists of a family of at least seven variants with 60-90 mol % serine most of which is phosphorylated in the cement. Pc-1, -2, and -3 contain cysteine some of which reacts to form 5-S-cysteinyl-Dopa cross-links during the setting process.

Mapping chemical gradients within and along a fibrous structural tissue, mussel byssal threads.

The byssal thread of a mussel is an extraorganismic connective tissue that exhibits a striking end-to-end gradient in mechanical properties and thus provides a unique opportunity for studying how gradients are made. Mfp-1 (Mytilus foot protein-1) is a conspicuous component of the protective outer cuticle of byssal threads given its high 3,4-dihydroxyphenylalanine (Dopa) content at 10-15 mol %. Amino acid analysis of mfp-1 extracted from successive foot sections of Mytilus galloprovincialis reveals a post-translationally mediated gradient with highest Dopa levels present in mfp-1 from the accessory gland near the tip of the foot decreasing gradually toward the base. The Dopa content of successive segments of byssal threads decreases from the distal to the proximal end and thus reflects the trend of mfp-1 in the foot. Inductively coupled plasma analysis indicates that certain metal ions including iron follow the trend in Dopa along the thread. Energy-dispersive x-ray spectrometry showed that iron, when present, was concentrated in the cuticle of the threads but sparse in the core. The axial iron gradient appears most closely correlated with the Dopa gradient. The direct incubation of mussels and byssal threads in Fe(3+) supplemented seawater showed that byssal threads are unable to sequester iron from the seawater. Instead, particulate/soluble iron is actively taken up by mussels during filter feeding and incorporated into byssal threads during their secretion. Our results suggest that mussels may exploit the interplay between Dopa and metals to tailor the different parts of threads for specific mechanical properties.